47 results on '"Matrone N"'
Search Results
2. A39 - The acquired resistance to the combination of the anti-EGFR cetuximab and the MEK-inhibitor refametinib in KRAS mutated colorectal cancer cell lines depends on PI3K-signalling
- Author
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Vitiello, P.P., Viscardi, G., Martini, G., Cardone, C., Ciardiello, D., Belli, V., Matrone, N., Troiani, T., Napolitano, S., Sforza, V., De Falco, V., Giunta, E., Morgillo, F., Diadema, M.R., Vitale, P., Zanaletti, N., Ciardiello, F., and Martinelli, E.
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- 2017
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3. AXL is a predictor of poor survival and of resistance to anti-EGFR therapy in RAS wild-type metastatic colorectal cancer
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Cardone C., Blauensteiner B., Moreno-Viedma V., Martini G., Simeon V., Vitiello P. P., Ciardiello D., Belli V., Matrone N., Troiani T., Morgillo F., Zito Marino F., Dentice M., Nappi A., Boccaccino A., Antoniotti C., Cremolini C., Pietrantonio F., Prager G. W., Normanno N., Maiello E., Argiles G., Elez E., Signoriello G., Franco R., Falcone A., Tabernero J., Sibilia M., Ciardiello F., Martinelli E., ZITO MARINO, Federica, Cardone, Claudia, Blauensteiner, Bernadette, Moreno-Viedma, Veronica, Martini, Giulia, Simeon, Vittorio, Vitiello, Pietro P, Ciardiello, Davide, Belli, Valentina, Matrone, Nunzia, Troiani, Teresa, Morgillo, Floriana, Zito Marino, Federica, Dentice, Monica, Nappi, Annarita, Boccaccino, Alessandra, Antoniotti, Carlotta, Cremolini, Chiara, Pietrantonio, Filippo, Prager, Gerald W, Normanno, Nicola, Maiello, Evaristo, Argiles, Guillem, Elez, Elena, Signoriello, Giuseppe, Franco, Renato, Falcone, Alfredo, Tabernero, Josep, Sibilia, Maria, Ciardiello, Fortunato, Martinelli, Erika, Cardone, C., Blauensteiner, B., Moreno-Viedma, V., Martini, G., Simeon, V., Vitiello, P. P., Ciardiello, D., Belli, V., Matrone, N., Troiani, T., Morgillo, F., Zito Marino, F., Dentice, M., Nappi, A., Boccaccino, A., Antoniotti, C., Cremolini, C., Pietrantonio, F., Prager, G. W., Normanno, N., Maiello, E., Argiles, G., Elez, E., Signoriello, G., Franco, R., Falcone, A., Tabernero, J., Sibilia, M., Ciardiello, F., Martinelli, E., and ZITO MARINO, Federica
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Colorectal cancer ,Population ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Growth factor receptor ,Internal medicine ,Cell Line, Tumor ,Proto-Oncogene Proteins ,Medicine ,Animals ,Humans ,Epithelial–mesenchymal transition ,Neoplasm Metastasis ,education ,education.field_of_study ,Cetuximab ,business.industry ,AXL ,EGFR resistance ,RAS WT ,Receptor Protein-Tyrosine Kinases ,Transfection ,medicine.disease ,Xenograft Model Antitumor Assays ,Axl Receptor Tyrosine Kinase ,Blockade ,ErbB Receptors ,030104 developmental biology ,Genes, ras ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Immunohistochemistry ,business ,Colorectal Neoplasms ,Biomarkers ,medicine.drug - Abstract
Background RAS mutations are the only validated biomarkers in metastatic colorectal cancer (mCRC) for anti-epidermal growth factor receptor (EGFR) therapy. Limited clinical information is available on AXL expression, marker of epithelial to mesenchymal transition, in mCRC. Methods AXL was retrospectively assessed by immunohistochemistry in 307 patients. RAS wild-type (WT) patients (N = 136) received first-line anti-EGFR–based therapy; RAS mutant patients (N = 171) received anti-angiogenic–based regimens. Preclinical experiments were performed using human RAS WT CRC cell lines and xenograft models. AXL RNA levels were assessed in a cohort of patients with available samples at baseline and at progression to anti-EGFR treatment and in the GSE5851 dataset. Results AXL was expressed in 55/307 tumour tissues, correlating with worse survival in the overall population (AXL-positive, 23.7 months; AXL-negative, 30.8 months; HR, 1.455, P = 0.032) and in RAS WT patients (AXL-positive, 23.0 months; AXL-negative, 35.8 months; HR,1.780, P = 0.032). Progression-free survival (PFS) in the RAS WT cohort was shorter in the AXL-positive cohort (6.2 months versus 12.1 months; HR, 1.796, P = 0.013). Three-dimensional cultures obtained from a patient following anti-EGFR therapy resulted AXL-positive, showing resistance to anti-EGFR drugs and sensitivity to AXL inhibition. AXL transfection in CRC cell lines induced AXL overexpression and resistance to the EGFR blockade. At progression to cetuximab, 2/10 SW48-tumour xenograft mice showed AXL expression. Consistently, AXL RNA levels increased in 5/7 patients following anti-EGFR therapy. Moreover, in the GSE5851 dataset higher AXL RNA levels correlated with worse PFS with cetuximab in KRAS-exon2 WT chemorefractory patients. Conclusions AXL is a marker of poor prognosis in mCRC with consistent clinical and preclinical evidences of involvement in primary and acquired resistance to anti-EGFR drugs in RAS WT patients.
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- 2020
4. 1951P Niraparib and irinotecan combination in ATM-mutated colorectal cancer
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Vitiello, P.P., primary, Martini, G., additional, Mele, L., additional, Giunta, E.F., additional, De Falco, V., additional, Ciardiello, D., additional, Belli, V., additional, Cardone, C., additional, Matrone, N., additional, Poliero, L., additional, Tirino, V., additional, Selvaggi, F., additional, Papaccio, G., additional, Troiani, T., additional, Desiderio, V., additional, Ciardiello, F., additional, and Martinelli, E., additional
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- 2020
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5. Dual inhibition of TGF-β and AXL as a novel treatment for colorectal cancer
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Ciardiello, D., primary, Belli, V., additional, Cardone, C., additional, Vitiello, P.P., additional, Martini, G., additional, Poliero, L., additional, Borrelli, C., additional, Arrichiello, G., additional, Ciaramella, V., additional, Matrone, N., additional, Barra, G., additional, De Falco, V., additional, Giunta, E.F., additional, Morgillo, F., additional, Troiani, T., additional, Terminiello, M., additional, Melisi, D., additional, Ciardiello, F., additional, and Martinelli, E., additional
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- 2019
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6. Triple blockade of EGFR, MEK and PD-L1 as effective antitumor treatment in PD-L1 overexpressing, MEK inhibitor resistant colon cancer cells
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Matrone, N., primary, Napolitano, S., additional, Belli, V., additional, Barra, G., additional, Giunta, E.F., additional, De Falco, V., additional, Terminiello, M., additional, Vitiello, P.P., additional, Ciardiello, D., additional, Turano, M., additional, Furia, M., additional, Muddassir, A.S., additional, Kopetz, S., additional, Martinelli, E., additional, Ciardiello, F., additional, and Troiani, T., additional
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- 2019
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7. A new natural compound identified through a metabolomic approach has cytotoxic activity against human colorectal cancer cell lines with acquired resistance to cetuximab
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De Falco, V., primary, Giunta, E.F., additional, Belli, V., additional, Matrone, N., additional, Napolitano, S., additional, Martinelli, E., additional, Vitale, P., additional, Zanaletti, N., additional, Terminiello, M., additional, Vitiello, P.P., additional, Ciardiello, F., additional, and Troiani, T., additional
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- 2018
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8. Functional inhibition of TGF-β in colorectal cancer cells and its interaction with AXL receptor
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Ciardiello, D., primary, Martini, G., additional, Matrone, N., additional, Belli, V., additional, Vitiello, P.P., additional, Cardone, C., additional, Ciaramella, V., additional, Barra, G., additional, Poliero, L., additional, Borrelli, C., additional, Troiani, T., additional, Melisi, D., additional, Morgillo, F., additional, Giunta, E.F., additional, De Falco, V., additional, Ciardiello, F., additional, and Martinelli, E., additional
- Published
- 2018
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9. Combination treatment with the PARP inhibitor niraparib and chemotherapeutics in a preclinical model of KRAS/BRAF mutated colorectal cancer cell lines across the four consensus molecular subtypes
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Vitiello, P.P., primary, Cardone, C., additional, Ciardiello, D., additional, Belli, V., additional, Matrone, N., additional, Borrelli, C., additional, Poliero, L., additional, De Falco, V., additional, Giunta, E.F., additional, Vitale, P., additional, Zanaletti, N., additional, Tirino, G., additional, Troiani, T., additional, Ciardiello, F., additional, and Martinelli, E., additional
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- 2018
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10. Macrophage migration inhibitory factor overexpression is a mechanism of acquired resistance to anti-EGFR inhibitor cetuximab in human colorectal cancer cell line
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Matrone, N., primary, Chambery, A., additional, Russo, R., additional, Pedone, P.V., additional, Belli, V., additional, Napolitano, S., additional, Martinelli, E., additional, Giunta, E.F., additional, De Falco, V., additional, Zanaletti, N., additional, Vitale, P., additional, Terminiello, M., additional, Cardone, C., additional, Ciardiello, F., additional, and Troiani, T., additional
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- 2018
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11. Receptor tyrosine kinase dependent PI3K activation is an escape mechanism to vertical suppression of the EGFR/RAS/MAPK pathway in KRAS-mutated colorectal cancer cell lines
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Vitiello, P.P., primary, Cardone, C., additional, Ciardiello, D., additional, Barra, G., additional, Matrone, N., additional, Belli, V., additional, Martini, G., additional, Poliero, L., additional, Borrelli, C., additional, Terminiello, M., additional, Troiani, T., additional, Morgillo, F., additional, Ciardiello, F., additional, and Martinelli, E., additional
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- 2018
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12. Combined inhibition of MEK and PI3KCA pathway induces synergic antitumor activity in HER2 amplified human colorectal cancer models
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Belli, V., primary, Matrone, N., additional, Napolitano, S., additional, Martinelli, E., additional, Castellone, M.D., additional, Trusolino, L., additional, Giunta, E.F., additional, De Falco, V., additional, Zanaletti, N., additional, Vitiello, P.P., additional, Ciardiello, D., additional, Terminiello, M., additional, Ciardiello, F., additional, and Troiani, T., additional
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- 2018
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13. PO-519 Combined inhibition of MEK and PI3KCA pathway induces synergic antitumor activity in HER2 amplified colorectal cancer models
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Belli, V., primary, Matrone, N., additional, Castellone, M., additional, Napolitano, S., additional, Martinelli, E., additional, Morgillo, F., additional, Ciardiello, F., additional, and Troiani, T., additional
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- 2018
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14. EPHA2 receptor is involved in in vivo acquired resistance to anti-epidermal growth factor receptor (EGFR) treatment in metastatic colorectal cancer
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Martini, G., primary, Belli, V., additional, Vitiello, P.P., additional, Troiani, T., additional, Cardone, C., additional, Napolitano, S., additional, Matrone, N., additional, Sforza, V., additional, Savastano, B., additional, Renato, F., additional, Morgillo, F., additional, Della Corte, C.M., additional, Ciardiello, D., additional, Giunta, E.F., additional, De Falco, V., additional, Zanaletti, N., additional, Vitale, P., additional, Ciardiello, F., additional, and Martinelli, E., additional
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- 2017
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15. The acquired resistance to the combination of the anti-EGFR cetuximab and the MEK-inhibitor refametinib in KRAS mutated colorectal cancer cell lines depends on PI3K-signalling
- Author
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Vitiello, P.P., primary, Viscardi, G., additional, Martini, G., additional, Cardone, C., additional, Ciardiello, D., additional, Belli, V., additional, Matrone, N., additional, Troiani, T., additional, Napolitano, S., additional, Sforza, V., additional, De Falco, V., additional, Giunta, E., additional, Morgillo, F., additional, Diadema, M.R., additional, Vitale, P., additional, Zanaletti, N., additional, Ciardiello, F., additional, and Martinelli, E., additional
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- 2017
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16. Antitumor efficacy of triple monoclonal antibody inhibition of epidermal growth factor receptor (EGFR) with MM-151 in EGFR-dependent and in cetuximab-resistant human colorectal cancer cells
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Napolitano, S., primary, Martini, G., additional, Martinelli, E., additional, Della Corte, C.M., additional, Belli, V., additional, Matrone, N., additional, Morgillo, F., additional, Ciardiello, F., additional, and Troiani, T., additional
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- 2017
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17. 66P - Dual inhibition of TGF-β and AXL as a novel treatment for colorectal cancer
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Ciardiello, D., Belli, V., Cardone, C., Vitiello, P.P., Martini, G., Poliero, L., Borrelli, C., Arrichiello, G., Ciaramella, V., Matrone, N., Barra, G., De Falco, V., Giunta, E.F., Morgillo, F., Troiani, T., Terminiello, M., Melisi, D., Ciardiello, F., and Martinelli, E.
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- 2019
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18. 11P - Triple blockade of EGFR, MEK and PD-L1 as effective antitumor treatment in PD-L1 overexpressing, MEK inhibitor resistant colon cancer cells
- Author
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Matrone, N., Napolitano, S., Belli, V., Barra, G., Giunta, E.F., De Falco, V., Terminiello, M., Vitiello, P.P., Ciardiello, D., Turano, M., Furia, M., Muddassir, A.S., Kopetz, S., Martinelli, E., Ciardiello, F., and Troiani, T.
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- 2019
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19. 598P - Macrophage migration inhibitory factor overexpression is a mechanism of acquired resistance to anti-EGFR inhibitor cetuximab in human colorectal cancer cell line
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Matrone, N., Chambery, A., Russo, R., Pedone, P.V., Belli, V., Napolitano, S., Martinelli, E., Giunta, E.F., De Falco, V., Zanaletti, N., Vitale, P., Terminiello, M., Cardone, C., Ciardiello, F., and Troiani, T.
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- 2018
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20. 596P - Combined inhibition of MEK and PI3KCA pathway induces synergic antitumor activity in HER2 amplified human colorectal cancer models
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Belli, V., Matrone, N., Napolitano, S., Martinelli, E., Castellone, M.D., Trusolino, L., Giunta, E.F., De Falco, V., Zanaletti, N., Vitiello, P.P., Ciardiello, D., Terminiello, M., Ciardiello, F., and Troiani, T.
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- 2018
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21. 33P - A new natural compound identified through a metabolomic approach has cytotoxic activity against human colorectal cancer cell lines with acquired resistance to cetuximab
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De Falco, V., Giunta, E.F., Belli, V., Matrone, N., Napolitano, S., Martinelli, E., Vitale, P., Zanaletti, N., Terminiello, M., Vitiello, P.P., Ciardiello, F., and Troiani, T.
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- 2018
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22. 25P - Functional inhibition of TGF-β in colorectal cancer cells and its interaction with AXL receptor
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Ciardiello, D., Martini, G., Matrone, N., Belli, V., Vitiello, P.P., Cardone, C., Ciaramella, V., Barra, G., Poliero, L., Borrelli, C., Troiani, T., Melisi, D., Morgillo, F., Giunta, E.F., De Falco, V., Ciardiello, F., and Martinelli, E.
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- 2018
- Full Text
- View/download PDF
23. 18P - Combination treatment with the PARP inhibitor niraparib and chemotherapeutics in a preclinical model of KRAS/BRAF mutated colorectal cancer cell lines across the four consensus molecular subtypes
- Author
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Vitiello, P.P., Cardone, C., Ciardiello, D., Belli, V., Matrone, N., Borrelli, C., Poliero, L., De Falco, V., Giunta, E.F., Vitale, P., Zanaletti, N., Tirino, G., Troiani, T., Ciardiello, F., and Martinelli, E.
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- 2018
- Full Text
- View/download PDF
24. 2O - Receptor tyrosine kinase dependent PI3K activation is an escape mechanism to vertical suppression of the EGFR/RAS/MAPK pathway in KRAS-mutated colorectal cancer cell lines
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Vitiello, P.P., Cardone, C., Ciardiello, D., Barra, G., Matrone, N., Belli, V., Martini, G., Poliero, L., Borrelli, C., Terminiello, M., Troiani, T., Morgillo, F., Ciardiello, F., and Martinelli, E.
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- 2018
- Full Text
- View/download PDF
25. A34 - EPHA2 receptor is involved in in vivo acquired resistance to anti-epidermal growth factor receptor (EGFR) treatment in metastatic colorectal cancer
- Author
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Martini, G., Belli, V., Vitiello, P.P., Troiani, T., Cardone, C., Napolitano, S., Matrone, N., Sforza, V., Savastano, B., Renato, F., Morgillo, F., Della Corte, C.M., Ciardiello, D., Giunta, E.F., De Falco, V., Zanaletti, N., Vitale, P., Ciardiello, F., and Martinelli, E.
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- 2017
- Full Text
- View/download PDF
26. 1636P - EPHA2 receptor is involved in in vivo acquired resistance to anti-Epidermal Growth Factor Receptor (EGFR) treatment in metastatic colorectal cancer (mCRC)
- Author
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Martini, G., Belli, V., Vitiello, P.P., Troiani, T., Cardone, C., Napolitano, S., Matrone, N., Sforza, V., Franco, R., Morgillo, F., Ciardiello, D., Giunta, E., De Falco, V., Zanaletti, N., Vitale, P., Martinelli, E., and Ciardiello, F.
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- 2017
- Full Text
- View/download PDF
27. 407P - Antitumor efficacy of triple monoclonal antibody inhibition of epidermal growth factor receptor (EGFR) with MM-151 in EGFR-dependent and in cetuximab-resistant human colorectal cancer cells
- Author
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Napolitano, S., Martini, G., Martinelli, E., Della Corte, C.M., Belli, V., Matrone, N., Morgillo, F., Ciardiello, F., and Troiani, T.
- Published
- 2017
- Full Text
- View/download PDF
28. 5PD - The acquired resistance to the combination of the anti-EGFR cetuximab and the MEK-inhibitor refametinib in KRAS mutated colorectal cancer cell lines depends on PI3K-signalling
- Author
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Vitiello, P.P., Martini, G., Cardone, C., Ciardiello, D., Belli, V., Matrone, N., Troiani, T., Napolitano, S., Sforza, V., Papaccio, G., Desiderio, V., De Falco, V., Giunta, E., Morgillo, F., Diadema, M.R., Vitale, P., Zanaletti, N., Ciardiello, F., and Martinelli, E.
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- 2017
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29. Triple blockade of EGFR, MEK and PD-L1 has antitumor activity in colorectal cancer models with constitutive activation of MAPK signaling and PD-L1 overexpression
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Maria Furia, Teresa Troiani, Fortunato Ciardiello, A. L. Muddassir, Floriana Morgillo, V. De Falco, Alexey V. Sorokin, Stefania Napolitano, Emilio Francesco Giunta, Valentina Belli, Erika Martinelli, Giulia Martini, Scott Kopetz, Davide Ciardiello, Nunzia Matrone, Institut Català de la Salut, [Napolitano S] Medical Oncology Department of Precision Medicine, University of Campania 'Luigi Vanvitelli', 80100 Naples, Italy. Department of Gastrointestinal Medical Oncology, Division of Cancer Medicin0065, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. [Matrone N] Medical Oncology Department of Precision Medicine, University of Campania 'Luigi Vanvitelli', 80100 Naples, Italy. Medical University of Vienna, Institute for Cancer Research, Borschkegasse 8A, 1090 Wien, Austria. [Muddassir AL, Sorokin A] Department of Gastrointestinal Medical Oncology, Division of Cancer Medicin0065, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. [Martini G] Medical Oncology Department of Precision Medicine, University of Campania 'Luigi Vanvitelli', 80100 Naples, Italy. Gastrointestinal and neuroendocrine tumor group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [De Falco V] Medical Oncology Department of Precision Medicine, University of Campania 'Luigi Vanvitelli', 80100 Naples, Italy, Hospital Universitari Vall d'Hebron, Napolitano, S., Matrone, N., Muddassir, A. L., Martini, G., Sorokin, A., De Falco, V., Giunta, E. F., Ciardiello, D., Martinelli, E., Belli, V., Furia, M., Kopetz, S., Morgillo, F., Ciardiello, F., Troiani, T., and Vall d'Hebron Barcelona Hospital Campus
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0301 basic medicine ,Neuroblastoma RAS viral oncogene homolog ,Cancer Research ,Colorectal cancer ,medicine.disease_cause ,B7-H1 Antigen ,0302 clinical medicine ,Còlon - Càncer ,MEK inhibitor resistance ,PD-L1 inhibitors ,EGFR inhibitors ,Sulfonamides ,biology ,Otros calificadores::Otros calificadores::/genética [Otros calificadores] ,MEK inhibitor ,Antibodies, Monoclonal ,MAP Kinase Kinase Kinases ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias intestinales::neoplasias colorrectales [ENFERMEDADES] ,ErbB Receptors ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Recte - Càncer ,Female ,KRAS ,Colorectal Neoplasms ,Epithelial-Mesenchymal Transition ,Physiological Phenomena::Pharmacological and Toxicological Phenomena::Pharmacological Phenomena::Drug Resistance::Drug Resistance, Neoplasm [PHENOMENA AND PROCESSES] ,MAP Kinase Signaling System ,lcsh:RC254-282 ,Erlotinib Hydrochloride ,03 medical and health sciences ,Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms [DISEASES] ,Cell Line, Tumor ,PD-L1 ,medicine ,Other subheadings::Other subheadings::/genetics [Other subheadings] ,Humans ,Resistència als medicaments ,fenómenos fisiológicos::fenómenos farmacológicos y toxicológicos::fenómenos farmacológicos::resistencia a medicamentos::resistencia a los antineoplásicos [FENÓMENOS Y PROCESOS] ,Research ,Diphenylamine ,Cancer ,Gene signature ,HCT116 Cells ,medicine.disease ,Xenograft Model Antitumor Assays ,030104 developmental biology ,Drug Resistance, Neoplasm ,biology.protein ,Cancer research - Abstract
Background Molecular mechanisms driving acquired resistance to anti-EGFR therapies in metastatic colorectal cancer (mCRC) are complex but generally involve the activation of the downstream RAS-RAF-MEK-MAPK pathway. Nevertheless, even if inhibition of EGFR and MEK could be a strategy for overcoming anti-EGFR resistance, its use is limited by the development of MEK inhibitor (MEKi) resistance. Methods We have generated in vitro and in vivo different CRC models in order to underline the mechanisms of MEKi resistance. Results The three different in vitro MEKi resistant models, two generated by human CRC cells quadruple wild type for KRAS, NRAS, BRAF, PI3KCA genes (SW48-MR and LIM1215-MR) and one by human CRC cells harboring KRAS mutation (HCT116-MR) showed features related to the gene signature of colorectal cancer CMS4 with up-regulation of immune pathway as confirmed by microarray and western blot analysis. In particular, the MEKi phenotype was associated with the loss of epithelial features and acquisition of mesenchymal markers and morphology. The change in morphology was accompanied by up-regulation of PD-L1 expression and activation of EGFR and its downstream pathway, independently to RAS mutation status. To extend these in vitro findings, we have obtained mouse colon cancer MC38- and CT26-MEKi resistant syngeneic models (MC38-MR and CT26-MR). Combined treatment with MEKi, EGFR inhibitor (EGFRi) and PD-L1 inhibitor (PD-L1i) resulted in a marked inhibition of tumor growth in both models. Conclusions These results suggest a strategy to potentially improve the efficacy of MEK inhibition by co-treatment with EGFR and PD-L1 inhibitors via modulation of host immune responses.
- Published
- 2019
30. Vulnerability to low-dose combination of irinotecan and niraparib in ATM-mutated colorectal cancer
- Author
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Valentina Belli, Stefania Napolitano, Virginia Tirino, Pietro Paolo Vitiello, Emilio Francesco Giunta, Nunzia Matrone, Carminia Maria Della Corte, Vincenzo Desiderio, Giulia Martini, Claudia Cardone, Davide Ciardiello, Luigi Mele, L. Poliero, Floriana Morgillo, Vincenzo De Falco, Fortunato Ciardiello, Teresa Troiani, Erika Martinelli, Francesco Selvaggi, Gianpaolo Papaccio, Vitiello, P. P., Martini, G., Mele, L., Giunta, E. F., De Falco, V., Ciardiello, D., Belli, V., Cardone, C., Matrone, N., Poliero, L., Tirino, V., Napolitano, S., Della Corte, C., Selvaggi, F., Papaccio, G., Troiani, T., Morgillo, F., Desiderio, V., Ciardiello, F., and Martinelli, E.
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0301 basic medicine ,Cancer Research ,Indazoles ,Colorectal cancer ,DNA damage ,medicine.medical_treatment ,Mice, Nude ,DNA damage response ,Irinotecan ,lcsh:RC254-282 ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Piperidines ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Animals ,Humans ,Homologous recombination ,Clonogenic assay ,PARP inhibitors ,Chemotherapy ,business.industry ,Research ,Synergism ,Drug interaction ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,digestive system diseases ,Oxaliplatin ,030104 developmental biology ,PARP inhibitor ,Oncology ,030220 oncology & carcinogenesis ,Combination treatment ,Mutation ,Chemopotentiation ,Cancer research ,Female ,business ,Colorectal Neoplasms ,medicine.drug - Abstract
Background Despite the advancements in new therapies for colorectal cancer (CRC), chemotherapy still constitutes the mainstay of the medical treatment. For this reason, new strategies to increase the efficacy of chemotherapy are desirable. Poly-ADP-Ribose Polymerase inhibitors (PARPi) have shown to increase the activity of DNA damaging chemotherapeutics used in the treatment of CRC, however previous clinical trials failed to validate these results and pointed out dose-limiting toxicities that hamper the use of such combinations in unselected CRC patients. Nevertheless, in these studies little attention was paid to the mutational status of homologous recombination repair (HRR) genes. Methods We tested the combination of the PARPi niraparib with either 5-fluorouracil, oxaliplatin or irinotecan (SN38) in a panel of 12 molecularly annotated CRC cell lines, encompassing the 4 consensus molecular subtypes (CMSs). Synergism was calculated using the Chou-Talalay method for drug interaction. A correlation between synergism and genetic alterations in genes involved in homologous recombination (HR) repair was performed. We used clonogenic assays, mice xenograft models and patient-derived 3D spheroids to validate the results. The induction of DNA damage was studied by immunofluorescence. Results We showed that human CRC cell lines, as well as patient-derived 3D spheroids, harboring pathogenic ATM mutations are significantly vulnerable to PARPi/chemotherapy combination at low doses, regardless of consensus molecular subtypes (CMS) and microsatellite status. The strongest synergism was shown for the combination of niraparib with irinotecan, and the presence of ATM mutations was associated to a delay in the resolution of double strand breaks (DSBs) through HRR and DNA damage persistence. Conclusions This work demonstrates that a numerically relevant subset of CRCs carrying heterozygous ATM mutations may benefit from the combination treatment with low doses of niraparib and irinotecan, suggesting a new potential approach in the treatment of ATM-mutated CRC, that deserves to be prospectively validated in clinical trials.
- Published
- 2021
31. Macrophage Migration Inhibitory Factor Is a Molecular Determinant of the Anti-EGFR Monoclonal Antibody Cetuximab Resistance in Human Colorectal Cancer Cells
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Valentina Belli, Fortunato Ciardiello, Mariangela Valletta, Teresa Troiani, Paolo V. Pedone, Sabrina Esposito, Nunzia Matrone, Davide Ciardiello, Rosita Russo, Angela Chambery, Russo, R., Matrone, N., Belli, V., Ciardiello, D., Valletta, M., Esposito, S., Pedone, P. V., Ciardiello, F., Troiani, T., and Chambery, A.
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Cancer Research ,Colorectal cancer ,medicine.drug_class ,colorectal cancer ,Drug resistance ,Monoclonal antibody ,lcsh:RC254-282 ,Article ,cetuximab ,medicine ,mass spectrometry (MS) ,Protein kinase B ,neoplasms ,drug resistance ,Cetuximab ,Cell growth ,business.industry ,MIF ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,digestive system diseases ,Oncology ,Cancer research ,Macrophage migration inhibitory factor ,Signal transduction ,business ,medicine.drug - Abstract
The clinical impact of the monoclonal antibody cetuximab targeting the EGFR in colorectal cancer (CRC) is widely recognized. Nevertheless, the onset of cetuximab resistance is a serious issue that limits the effectiveness of this drug in targeted therapies. Unraveling the molecular players involved in cancer resistance is the first step towards the identification of alternative signaling pathways that can be targeted to circumvent resistance mechanisms restoring the efficacy of therapeutic treatments in a tailored manner. Background: The clinical impact of the monoclonal antibody cetuximab targeting the EGFR in colorectal cancer (CRC) is widely recognized. Nevertheless, the onset of cetuximab resistance is a serious issue that limits the eddectiveness of this drug in targeted therapies. Unraveling the molecular players involved in cancer resistance is the first step towards the identification of alternative signaling pathways that can be targeted to circumvent resistance mechanisms restoring the efficacy of therapeutic treatments in a tailored manner. Methods: By applying a nanoLC-MS/MS TMT isobaric labeling-based approach, we have delineated a molecular hallmark of cetuximab-resistance in CRC. Results: We identified macrophage migration inhibitory factor (MIF) as a molecular determinant capable of triggering cancer resistance in sensitive human CRC cells. Blocking the MIF axis in resistant cells by a selective MIF inhibitor restores cell sensitivity to cetuximab. The combined treatment with cetuximab and the MIF inhibitor further enhanced cell growth inhibition in CRC resistant cell lines with a synergistic effect depending on inhibition of key downstream effectors of the MAPK and AKT signaling pathways. Conclusions: Collectively, our results suggest the association of MIF signaling and its dysregulation to cetuximab drug resistance, paving the way to the development of personalized combination therapies targeting the MIF axis.
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- 2019
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32. Combined blockade of MEK and PI3KCA as an effective antitumor strategy in HER2 gene amplified human colorectal cancer models
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Andrea Bertotti, Davide Ciardiello, Nunzia Matrone, Valentina Belli, Floriana Morgillo, Vincenzo De Falco, Erika Martinelli, Emilio Francesco Giunta, Fortunato Ciardiello, Livio Trusolino, Stefania Napolitano, Umberto Bracale, Giorgia Migliardi, Francesca Cottino, Teresa Troiani, Belli, V., Matrone, N., Napolitano, S., Migliardi, G., Cottino, F., Bertotti, A., Trusolino, L., Martinelli, E., Morgillo, F., Ciardiello, D., De Falco, V., Giunta, E. F., Bracale, U., Ciardiello, F., and Troiani, T.
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0301 basic medicine ,MAPK/ERK pathway ,Neuroblastoma RAS viral oncogene homolog ,MAP Kinase Kinase Kinase ,Cancer Research ,Transcription Factor ,Receptor, ErbB-2 ,Colorectal cancer ,Colorectal Neoplasm ,medicine.disease_cause ,Antineoplastic Agent ,Mice ,0302 clinical medicine ,Epidermal growth factor receptor ,skin and connective tissue diseases ,Nuclear Protein ,Cetuximab ,biology ,Nuclear Proteins ,MAP Kinase Kinase Kinases ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,HER2-amplified cancer ,MEK and PI3KCA inhibitors ,xenografts ,patient-derived xenografts ,Oncology ,030220 oncology & carcinogenesis ,Female ,Pertuzumab ,KRAS ,Colorectal Neoplasms ,Human ,medicine.drug ,patient-derived xenograft ,Xenograft Model Antitumor Assay ,MEK and PI3KCA inhibitor ,Protein Kinase Inhibitor ,Antineoplastic Agents ,Lapatinib ,lcsh:RC254-282 ,03 medical and health sciences ,Cell Line, Tumor ,Biomarkers, Tumor ,medicine ,Animals ,Humans ,xenograft ,Protein Kinase Inhibitors ,neoplasms ,Dose-Response Relationship, Drug ,Animal ,business.industry ,Research ,Gene Amplification ,medicine.disease ,Xenograft Model Antitumor Assays ,Disease Models, Animal ,030104 developmental biology ,Drug Resistance, Neoplasm ,Cancer research ,biology.protein ,business ,Transcription Factors - Abstract
Background Targeting the epidermal growth factor receptor (EGFR) either alone or in combination with chemotherapy is an effective treatment for patients with RAS wild-type metastatic colorectal cancer (mCRC). However, only a small percentage of mCRC patients receive clinical benefits from anti-EGFR therapies, due to the development of resistance mechanisms. In this regard, HER2 has emerged as an actionable target in the treatment of mCRC patients with resistance to anti-EGFR therapy. Methods We have used SW48 and LIM1215 human colon cancer cell lines, quadruple wild-type for KRAS, NRAS, BRAF and PI3KCA genes, and their HER2–amplified (LIM1215-HER2 and SW48-HER2) derived cells to perform in vitro and in vivo studies in order to identify novel therapeutic strategies in HER2 gene amplified human colorectal cancer. Results LIM1215-HER2 and SW48-HER2 cells showed over-expression and activation of the HER family receptors and concomitant intracellular downstream signaling including the pro-survival PI3KCA/AKT and the mitogenic RAS/RAF/MEK/MAPK pathways. HER2-amplified cells were treated with several agents including anti-EGFR antibodies (cetuximab, SYM004 and MM151); anti-HER2 (trastuzumab, pertuzumab and lapatinib) inhibitors; anti-HER3 (duligotuzumab) inhibitors; and MEK and PI3KCA inhibitors, such as refametinib and pictilisib, as single agents and in combination. Subsequently, different in vivo experiments have been performed. MEK plus PI3KCA inhibitors treatment determined the best antitumor activity. These results were validated in vivo in HER2-amplified patient derived tumor xenografts from three metastatic colorectal cancer patients. Conclusions These results suggest that combined therapy with MEK and PI3KCA inhibitors could represent a novel and effective treatment option for HER2-amplified colorectal cancer. Electronic supplementary material The online version of this article (10.1186/s13046-019-1230-z) contains supplementary material, which is available to authorized users.
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- 2019
33. Receptor tyrosine kinase-dependent PI3K activation is an escape mechanism to vertical suppression of the EGFR/RAS/MAPK pathway in KRAS-mutated human colorectal cancer cell lines
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Floriana Morgillo, Fortunato Ciardiello, Valentina Belli, Carmina Della Corte, Ferdinando De Vita, Pietro Paolo Vitiello, Giusi Barra, Erika Martinelli, Claudia Cardone, Stefania Napolitano, Maria Furia, Mimmo Turano, Giulia Martini, Nunzia Matrone, Davide Ciardiello, Teresa Troiani, Vitiello, Pietro Paolo, Cardone, Claudia, Martini, Giulia, Ciardiello, Davide, Belli, Valentina, Matrone, Nunzia, Barra, Giusi, Napolitano, Stefania, Della Corte, Carmina, Turano, Mimmo, Furia, Maria, Troiani, Teresa, Morgillo, Floriana, De Vita, Ferdinando, Ciardiello, Fortunato, Martinelli, Erika, Institut Català de la Salut, [Vitiello PP, Cardone C] Department of Precision Medicine, Università degli studi della Campania 'Luigi Vanvitelli', Naples, Italy. [Martini G] Department of Precision Medicine, Università degli studi della Campania 'Luigi Vanvitelli', Naples, Italy. Vall d'Hebron Institut d'Oncologia, Barcelona, Spain. [Ciardiello D, Belli V, Matrone N] Department of Precision Medicine, Università degli studi della Campania 'Luigi Vanvitelli', Naples, Italy., Vall d'Hebron Barcelona Hospital Campus, and Hospital Universitari Vall d'Hebron
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0301 basic medicine ,MAPK/ERK pathway ,Cancer Research ,Digestive System Diseases::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Digestive System Diseases::Digestive System Diseases::Digestive System Diseases::Digestive System Diseases::Colorectal Neoplasms [DISEASES] ,Apoptosis ,Hormones, Hormone Substitutes, and Hormone Antagonists::Hormones::Gastrointestinal Hormones::Epidermal Growth Factor [CHEMICALS AND DRUGS] ,medicine.disease_cause ,Receptor tyrosine kinase ,AKT inhibitor ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,Tumor cell biology ,Cell Movement ,Còlon - Càncer ,enzimas y coenzimas::enzimas::transferasas::fosfotransferasas::fosfotransferasas (grupo alcohol aceptor)::proteína cinasas::proteína-serina-treonina cinasas::MAP cinasa cinasa cinasas [COMPUESTOS QUÍMICOS Y DROGAS] ,Tumor Cells, Cultured ,Colorectal cancer ,Epidermal growth factor receptor (EGFR) ,MAPK pathway ,MEK inhibitor ,PI3K inhibitor ,PI3K pathway ,RAS mutation ,Vertical suppression ,Otros calificadores::Otros calificadores::/antagonistas & inhibidores [Otros calificadores] ,Phosphorylation ,Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Protein Kinases::Protein-Serine-Threonine Kinases::MAP Kinase Kinase Kinases [CHEMICALS AND DRUGS] ,Cetuximab ,biology ,Chemistry ,Factor de creixement epidèrmic - Inhibidors ,hormonas, sustitutos de hormonas y antagonistas de hormonas::hormonas::hormonas gastrointestinales::factor de crecimiento epidérmico [COMPUESTOS QUÍMICOS Y DROGAS] ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,ErbB Receptors ,Oncology ,030220 oncology & carcinogenesis ,Enfermedades del Sistema Digestivo::Neoplasias del Sistema Digestivo::Neoplasias Gastrointestinales::Neoplasias Intestinales::Enfermedades del Sistema Digestivo::Enfermedades del Sistema Digestivo::Enfermedades del Sistema Digestivo::Enfermedades del Sistema Digestivo::Neoplasias Colorrectales [ENFERMEDADES] ,KRAS ,Colorectal Neoplasms ,medicine.drug ,Other subheadings::Other subheadings::/antagonists & inhibitors [Other subheadings] ,MAP Kinase Signaling System ,lcsh:RC254-282 ,Other subheadings::Other subheadings::/microbiology [Other subheadings] ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,Proteïnes quinases activades per mitògens - Inhibidors ,medicine ,Biomarkers, Tumor ,Humans ,Autocrine signalling ,neoplasms ,Protein Kinase Inhibitors ,PI3K/AKT/mTOR pathway ,enfermedades del sistema digestivo::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias intestinales::enfermedades del sistema digestivo::enfermedades del sistema digestivo::enfermedades del sistema digestivo::enfermedades del sistema digestivo::neoplasias colorrectales [ENFERMEDADES] ,Insulin-like growth factor 1 receptor ,Cell Proliferation ,Enzimas y Coenzimas::Enzimas::Transferasas::Fosfotransferasas::Fosfotransferasas (Aceptor de Grupo Alcohol)::Proteínas Quinasas::Proteínas Serina-Treonina Quinasas::Quinasas Quinasa Quinasa PAM [COMPUESTOS QUÍMICOS Y DROGAS] ,Research ,digestive system diseases ,030104 developmental biology ,Drug Resistance, Neoplasm ,Mutation ,biology.protein ,Cancer research ,Otros calificadores::Otros calificadores::/microbiología [Otros calificadores] - Abstract
Colorectal cancer; Epidermal growth factor receptor (EGFR); MAPK pathway Càncer colorectal; Receptor epidèrmic de factor del creixement (EGFR); Via MAPK Cáncer colorrectal; Receptor epidérmico de factor del crecimiento (EGFR); Vía MAPK BACKGROUND: Previous studies showed that the combination of an anti-Epidermal growth factor (EGFR) and a MEK-inhibitor is able to prevent the onset of resistance to anti-EGFR monoclonal antibodies in KRAS-wild type colorectal cancer (CRC), while the same combination reverts anti-EGFR primary resistance in KRAS mutated CRC cell lines. However, rapid onset of resistance is a limit to combination therapies in KRAS mutated CRC. METHODS: We generated four different KRAS mutated CRC cell lines resistant to a combination of cetuximab (an anti-EGFR antibody) and refametinib (a selective MEK-inhibitor) after continuous exposure to increasing concentration of the drugs. We characterized these resistant cell lines by evaluating the expression and activation status of a panel of receptor tyrosine kinases (RTKs) and intracellular transducers by immunoblot and qRT-PCR. Oncomine comprehensive assay and microarray analysis were carried out to investigate new acquired mutations or transcriptomic adaptation, respectively, in the resistant cell lines. Immunofluorescence assay was used to show the localization of RTKs in resistant and parental clones. RESULTS: We found that PI3K-AKT pathway activation acts as an escape mechanism in cell lines with acquired resistance to combined inhibition of EGFR and MEK. AKT pathway activation is coupled to the activation of multiple RTKs such as HER2, HER3 and IGF1R, though its pharmacological inhibition is not sufficient to revert the resistant phenotype. PI3K pathway activation is mediated by autocrine loops and by heterodimerization of multiple receptors. CONCLUSIONS: PI3K activation plays a central role in the acquired resistance to the combination of anti-EGFR and MEK-inhibitor in KRAS mutated colorectal cancer cell lines. PI3K activation is cooperatively achieved through the activation of multiple RTKs such as HER2, HER3 and IGF1R.
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- 2019
34. A dynamic link between H/ACA snoRNP components and cytoplasmic stress granules
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Alberto Angrisani, Andrea Conte, Elio Pizzo, Maria Furia, Rosa Incarnato, Mimmo Turano, Serena Sagliocchi, Nunzia Matrone, Valentina Belli, Belli, V., Matrone, N., Sagliocchi, S., Incarnato, R., Conte, A., Pizzo, E., Turano, M., Angrisani, A., and Furia, M.
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0301 basic medicine ,Nucleolus ,Ribosome biogenesis ,Cell Cycle Proteins ,Dyskerin ,Cytoplasmic Granules ,03 medical and health sciences ,0302 clinical medicine ,Stress granule ,Ribonucleoproteins, Small Nucleolar ,Tumor Cells, Cultured ,Humans ,Small nucleolar RNA ,Nucleolu ,Molecular Biology ,Ribonucleoprotein ,Chemistry ,Stress response ,Nuclear Proteins ,Cell Biology ,Ribosome ,Cell biology ,030104 developmental biology ,Cajal body ,Cytoplasm ,030220 oncology & carcinogenesis ,HeLa Cells ,RNP bodie ,snoRNP - Abstract
Many cell stressors block protein translation, inducing formation of cytoplasmic aggregates. These aggregates, named stress granules (SGs), are composed by translationally stalled ribonucleoproteins and their assembly strongly contributes to cell survival. Composition and dynamics of SGs are thus important starting points for identifying critical factors of the stress response. In the present study we link components of the H/ACA snoRNP complexes, highly concentrated in the nucleoli and the Cajal bodies, to SG composition. H/ACA snoRNPs are composed by a core of four highly conserved proteins -dyskerin, Nhp2, Nop10 and Gar1- and are involved in several fundamental processes, including ribosome biogenesis, RNA pseudouridylation, stabilization of small nucleolar RNAs and telomere maintenance. By taking advantage of cells overexpressing a dyskerin splice variant undergoing a dynamic intracellular trafficking, we were able to show that H/ACA snoRNP components can participate in SG formation, this way contributing to the stress response and perhaps transducing signals from the nucleus to the cytoplasm. Collectively, our results show for the first time that H/ACA snoRNP proteins can have additional non-nuclear functions, either independently or interacting with each other, thus further strengthening the close relationship linking nucleolus to SG composition.
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- 2019
35. A functional connection between dyskerin and energy metabolism
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Nunzia Matrone, Alberto Angrisani, Valentina Belli, Nunzia Di Maio, Antonio Porcellini, Filippo Scialò, Mimmo Turano, Paolo A. Netti, Rosario Vicidomini, Maria Furia, Angrisani, Alberto, Matrone, Nunzia, Belli, Valentina, Vicidomini, Rosario, Di Maio, Nunzia, Turano, Mimmo, Scialò, Filippo, Netti, Paolo Antonio, Porcellini, Antonio, Furia, Maria, Angrisani, A., Matrone, N., Belli, V., Vicidomini, R., Di Maio, N., Turano, M., Scialo, F., Netti, P. A., Porcellini, A., and Furia, M.
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0301 basic medicine ,Gene isoform ,Short Communication ,Clinical Biochemistry ,Ribosome biogenesis ,Cell Cycle Proteins ,Biology ,HeLa Cell ,Biochemistry ,Dyskerin ,03 medical and health sciences ,Superoxides ,Cell Cycle Protein ,Humans ,Protein Isoforms ,Nuclear protein ,Small nucleolar RNA ,lcsh:QH301-705.5 ,Nuclear Protein ,Genetics ,lcsh:R5-920 ,Organic Chemistry ,Protein Isoform ,Superoxide ,Nuclear Proteins ,Energy metabolism ,DKC1 ,Cell biology ,Telomere ,Mitochondria ,ROS signaling ,030104 developmental biology ,lcsh:Biology (General) ,RNA splicing ,PRDX-2 ,lcsh:Medicine (General) ,Reactive Oxygen Specie ,Reactive Oxygen Species ,Nuclear localization sequence ,Human ,HeLa Cells ,Signal Transduction - Abstract
The human DKC1 gene encodes dyskerin, an evolutionarily conserved nuclear protein whose overexpression represents a common trait of many types of aggressive sporadic cancers. As a crucial component of the nuclear H/ACA snoRNP complexes, dyskerin is involved in a variety of essential processes, including telomere maintenance, splicing efficiency, ribosome biogenesis, snoRNAs stabilization and stress response. Although multiple minor dyskerin splicing isoforms have been identified, their functions remain to be defined. Considering that low-abundance splice variants could contribute to the wide functional repertoire attributed to dyskerin, possibly having more specialized tasks or playing significant roles in changing cell status, we investigated in more detail the biological roles of a truncated dyskerin isoform that lacks the C-terminal nuclear localization signal and shows a prevalent cytoplasmic localization. Here we show that this dyskerin variant can boost energy metabolism and improve respiration, ultimately conferring a ROS adaptive response and a growth advantage to cells. These results reveal an unexpected involvement of DKC1 in energy metabolism, highlighting a previously underscored role in the regulation of metabolic cell homeostasis., Graphical abstract fx1, Highlights • Human dyskerin is an evolutionary conserved component of nuclear H/ACA snoRNPs. • The functional role of a truncated dyskerin isoform (Iso3) is analyzed. • Iso3 overexpression boosts energy metabolism and induces a ROS adaptive response. • Iso3 connects dyskerin with mitochondrial functionality and redox homeostasis.
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- 2018
36. 33PA new natural compound identified through a metabolomic approach has cytotoxic activity against human colorectal cancer cell lines with acquired resistance to cetuximab.
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Falco, V De, Giunta, E F, Belli, V, Matrone, N, Napolitano, S, Martinelli, E, Vitale, P, Zanaletti, N, Terminiello, M, and Vitiello, P P
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COLORECTAL cancer , *CELL lines , *CANCER cells , *ADULT T-cell leukemia - Published
- 2018
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37. Dual inhibition of TGFβ and AXL as a novel therapy for human colorectal adenocarcinoma with mesenchymal phenotype.
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Ciardiello D, Blauensteiner B, Matrone N, Belli V, Mohr T, Vitiello PP, Martini G, Poliero L, Cardone C, Napolitano S, De Falco V, Giunta EF, Ciaramella V, Corte CD, Barra G, Selvaggi F, Franco R, Marino FZ, Cuomo A, Morgillo F, Troiani T, Sibilia M, Ciardiello F, and Martinelli E
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- Adenocarcinoma metabolism, Adenocarcinoma pathology, Aged, Cell Line, Tumor, Cell Movement, Colorectal Neoplasms metabolism, Colorectal Neoplasms pathology, Computational Biology methods, Databases, Genetic, Female, Gene Expression Regulation, Neoplastic, Humans, Male, Middle Aged, Neoplasm Recurrence, Local metabolism, Neoplasm Recurrence, Local pathology, Prognosis, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins metabolism, Receptor Protein-Tyrosine Kinases metabolism, Receptor, Transforming Growth Factor-beta Type II metabolism, Signal Transduction, Spheroids, Cellular, Axl Receptor Tyrosine Kinase, Adenocarcinoma drug therapy, Benzocycloheptenes pharmacology, Colorectal Neoplasms drug therapy, Epithelial-Mesenchymal Transition, Neoplasm Recurrence, Local drug therapy, Proto-Oncogene Proteins antagonists & inhibitors, Pyrazoles pharmacology, Quinolines pharmacology, Receptor Protein-Tyrosine Kinases antagonists & inhibitors, Receptor, Transforming Growth Factor-beta Type II antagonists & inhibitors, Triazoles pharmacology
- Abstract
A subset of colorectal cancer (CRC) with a mesenchymal phenotype (CMS4) displays an aggressive disease, with an increased risk of recurrence after surgery, reduced survival, and resistance to standard treatments. It has been shown that the AXL and TGFβ signaling pathways are involved in epithelial-to-mesenchymal transition, migration, metastatic spread, and unresponsiveness to targeted therapies. However, the prognostic role of the combination of these biomarkers and the anti-tumor effect of AXL and TGFβ inhibition in CRC still has to be assessed. To evaluate the role of AXL and TGFβ as negative biomarker in CRC, we conducted an in-depth in silico analysis of CRC samples derived from the Gene Expression Omnibus. We found that AXL and TGFβ receptors are upregulated in CMS4 tumors and are correlated with an increased risk of recurrence after surgery in stage II/III CRC and a reduced overall survival. Moreover, we showed that AXL receptor is differently expressed in human CRC cell lines. Dual treatment with the TGFβ galunisertib and the AXL inhibitor, bemcentinib, significantly reduced colony formation and migration capabilities of tumor cells and displayed a strong anti-tumor activity in 3D spheroid cultures derived from patients with advanced CRC. Our work shows that AXL and TGFβ receptors identify a subgroup of CRC with a mesenchymal phenotype and correlate with poor prognosis. Dual inhibition of AXL and TGFβ could represent a novel therapeutic strategy for patients with this aggressive disease.
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- 2021
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38. Vulnerability to low-dose combination of irinotecan and niraparib in ATM-mutated colorectal cancer.
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Vitiello PP, Martini G, Mele L, Giunta EF, De Falco V, Ciardiello D, Belli V, Cardone C, Matrone N, Poliero L, Tirino V, Napolitano S, Della Corte C, Selvaggi F, Papaccio G, Troiani T, Morgillo F, Desiderio V, Ciardiello F, and Martinelli E
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- Animals, Antineoplastic Combined Chemotherapy Protocols pharmacology, Cell Line, Tumor, Female, Humans, Indazoles pharmacology, Irinotecan pharmacology, Mice, Mice, Nude, Mutation, Piperidines pharmacology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Colorectal Neoplasms drug therapy, Indazoles therapeutic use, Irinotecan therapeutic use, Piperidines therapeutic use
- Abstract
Background: Despite the advancements in new therapies for colorectal cancer (CRC), chemotherapy still constitutes the mainstay of the medical treatment. For this reason, new strategies to increase the efficacy of chemotherapy are desirable. Poly-ADP-Ribose Polymerase inhibitors (PARPi) have shown to increase the activity of DNA damaging chemotherapeutics used in the treatment of CRC, however previous clinical trials failed to validate these results and pointed out dose-limiting toxicities that hamper the use of such combinations in unselected CRC patients. Nevertheless, in these studies little attention was paid to the mutational status of homologous recombination repair (HRR) genes., Methods: We tested the combination of the PARPi niraparib with either 5-fluorouracil, oxaliplatin or irinotecan (SN38) in a panel of 12 molecularly annotated CRC cell lines, encompassing the 4 consensus molecular subtypes (CMSs). Synergism was calculated using the Chou-Talalay method for drug interaction. A correlation between synergism and genetic alterations in genes involved in homologous recombination (HR) repair was performed. We used clonogenic assays, mice xenograft models and patient-derived 3D spheroids to validate the results. The induction of DNA damage was studied by immunofluorescence., Results: We showed that human CRC cell lines, as well as patient-derived 3D spheroids, harboring pathogenic ATM mutations are significantly vulnerable to PARPi/chemotherapy combination at low doses, regardless of consensus molecular subtypes (CMS) and microsatellite status. The strongest synergism was shown for the combination of niraparib with irinotecan, and the presence of ATM mutations was associated to a delay in the resolution of double strand breaks (DSBs) through HRR and DNA damage persistence., Conclusions: This work demonstrates that a numerically relevant subset of CRCs carrying heterozygous ATM mutations may benefit from the combination treatment with low doses of niraparib and irinotecan, suggesting a new potential approach in the treatment of ATM-mutated CRC, that deserves to be prospectively validated in clinical trials.
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- 2021
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39. AXL is a predictor of poor survival and of resistance to anti-EGFR therapy in RAS wild-type metastatic colorectal cancer.
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Cardone C, Blauensteiner B, Moreno-Viedma V, Martini G, Simeon V, Vitiello PP, Ciardiello D, Belli V, Matrone N, Troiani T, Morgillo F, Zito Marino F, Dentice M, Nappi A, Boccaccino A, Antoniotti C, Cremolini C, Pietrantonio F, Prager GW, Normanno N, Maiello E, Argiles G, Elez E, Signoriello G, Franco R, Falcone A, Tabernero J, Sibilia M, Ciardiello F, and Martinelli E
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- Animals, Biomarkers, Cell Line, Tumor, Colorectal Neoplasms chemistry, Colorectal Neoplasms mortality, Colorectal Neoplasms pathology, Drug Resistance, Neoplasm, Humans, Mice, Neoplasm Metastasis, Xenograft Model Antitumor Assays, Axl Receptor Tyrosine Kinase, Colorectal Neoplasms drug therapy, ErbB Receptors antagonists & inhibitors, Genes, ras, Proto-Oncogene Proteins analysis, Receptor Protein-Tyrosine Kinases analysis
- Abstract
Background: RAS mutations are the only validated biomarkers in metastatic colorectal cancer (mCRC) for anti-epidermal growth factor receptor (EGFR) therapy. Limited clinical information is available on AXL expression, marker of epithelial to mesenchymal transition, in mCRC., Methods: AXL was retrospectively assessed by immunohistochemistry in 307 patients. RAS wild-type (WT) patients (N = 136) received first-line anti-EGFR-based therapy; RAS mutant patients (N = 171) received anti-angiogenic-based regimens. Preclinical experiments were performed using human RAS WT CRC cell lines and xenograft models. AXL RNA levels were assessed in a cohort of patients with available samples at baseline and at progression to anti-EGFR treatment and in the GSE5851 dataset., Results: AXL was expressed in 55/307 tumour tissues, correlating with worse survival in the overall population (AXL-positive, 23.7 months; AXL-negative, 30.8 months; HR, 1.455, P = 0.032) and in RAS WT patients (AXL-positive, 23.0 months; AXL-negative, 35.8 months; HR,1.780, P = 0.032). Progression-free survival (PFS) in the RAS WT cohort was shorter in the AXL-positive cohort (6.2 months versus 12.1 months; HR, 1.796, P = 0.013). Three-dimensional cultures obtained from a patient following anti-EGFR therapy resulted AXL-positive, showing resistance to anti-EGFR drugs and sensitivity to AXL inhibition. AXL transfection in CRC cell lines induced AXL overexpression and resistance to the EGFR blockade. At progression to cetuximab, 2/10 SW48-tumour xenograft mice showed AXL expression. Consistently, AXL RNA levels increased in 5/7 patients following anti-EGFR therapy. Moreover, in the GSE5851 dataset higher AXL RNA levels correlated with worse PFS with cetuximab in KRAS-exon2 WT chemorefractory patients., Conclusions: AXL is a marker of poor prognosis in mCRC with consistent clinical and preclinical evidences of involvement in primary and acquired resistance to anti-EGFR drugs in RAS WT patients., Competing Interests: Conflict of interest statement TT reports advisory board for Amgen, Bayer, Merck, Novartis, Roche and Sanofi. FM reports advisory board for Lilly and MSD. ChCr reports personal fees from Roche, Amgen, Bayer and Servier, research funding from Merck Serono and consulting or advisory role for Roche, Bayer and Amgen. FP reports honoraria/speaker bureau from Amgen, Roche, Merck Serono, Lilly, Sanofi, Bayer and Servier and research grants from BMS. GWP reports personal fees from advisory boards and/or speaker's honorarium: Amgen, Bayer, BMS, Boston Biomedical, Celgene, Halozyme, Lilly, Merck Serono, Roche, Sanofi, Servier, Shire, MSD, Taiho and CECOG. NN reports personal financial interests as speaker's fee and/or advisory boards from MSD, Qiagen, Bayer, Biocartis, Incyte, Roche, BMS, Merck, Thermo Fisher, Boehringer Ingelheim, AstraZeneca, Sanofi and Eli Lilly; institutional financial interests (financial support to research projets) from Merck, Sysmex, Thermo Fisher, Qiagen, Roche, AstraZeneca and Biocartis; non-financial interests: President, International Quality Network for Pathology (IQN Path), President Elect, Italian Cancer Society (SIC). EvMa reports personal financial interests honoraria for advisory role for advisory board from: Astra Zeneca, Sanofi Genzyme, Servier, Celgene, Merck, Lilly and Roche; research grants from MSD and BSD; travel grants from Merck and Roche; institutional financial interests as financial support for clinical trials from Roche, Sanofi Genzyme, Teva and Merck. GA reports personal financial interests from Hoffman-La Roche, Bristol Myers Squibb, Bayer, Servier, Amgen, Merck Serono and Menarini; institutional financial interests from Bayer, Servier, Novartis, Boehringer Ingelheim, Boston Pharmaceuticals, Hoffman-La Roche and Genentech. EE reports personal financial interests, honoraria for advisory role, travel grants, research grants from Hoffman-La Roche, Sanofi Aventis, Amgen, Merck Serono and Servier, MSD; institutional financial interests from Hoffman-LaRoche, Sanofi Aventis, Amgen, Merck Serono, MSD, Boehringer Ingelheim, AbbVie, Array Pharmaceuticals, Pierre Fabre and Novartis. AF reports personal financial interests (advisory role/honoraria): Bayer, Bristol, Lilly, Merck, Pierre Fabre, Roche, Servier; institutional financial interests as financial support for clinical trials from AstraZeneca, Bayer, Bristol, Lilly, Merck, MSD, Novartis, Roche, Sanofi and Servier. JT reports scientific consultancy roles for Bayer, Boehringer Ingelheim, Chugai, Genentech, Inc., Ipsen, Lilly, MSD, Merck Serono, Merrimack, Merus, Novartis, Peptomyc, Pfizer, Rafael Pharmaceuticals, F. Hoffmann-La Roche Ltd, Sanofi, Seattle Genetics, Symphogen and Taiho. FC reports being in the advisory boards for Merck, Roche, Amgen, Bayer, Servier, Symphogen and Pfizer and research funding from Roche, Merck, Amgen, Bayer and Ipsen. ErMa reports being in the advisory boards for Amgen, Bayer, Merck, Roche, Sanofi and Servier and giving expert opinion for ESMO (European Society of Medical Oncology). ClCa, BB, VMV, GM, VS, PPV, DC, VB, NM, FZ, MD, AN, AB, CA, GS, RF and MS report no competing conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
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- 2020
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40. A dynamic link between H/ACA snoRNP components and cytoplasmic stress granules.
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Belli V, Matrone N, Sagliocchi S, Incarnato R, Conte A, Pizzo E, Turano M, Angrisani A, and Furia M
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- Cell Cycle Proteins genetics, Cell Cycle Proteins isolation & purification, HeLa Cells, Humans, Nuclear Proteins genetics, Nuclear Proteins isolation & purification, Tumor Cells, Cultured, Cell Cycle Proteins metabolism, Cytoplasmic Granules metabolism, Nuclear Proteins metabolism, Ribonucleoproteins, Small Nucleolar metabolism
- Abstract
Many cell stressors block protein translation, inducing formation of cytoplasmic aggregates. These aggregates, named stress granules (SGs), are composed by translationally stalled ribonucleoproteins and their assembly strongly contributes to cell survival. Composition and dynamics of SGs are thus important starting points for identifying critical factors of the stress response. In the present study we link components of the H/ACA snoRNP complexes, highly concentrated in the nucleoli and the Cajal bodies, to SG composition. H/ACA snoRNPs are composed by a core of four highly conserved proteins -dyskerin, Nhp2, Nop10 and Gar1- and are involved in several fundamental processes, including ribosome biogenesis, RNA pseudouridylation, stabilization of small nucleolar RNAs and telomere maintenance. By taking advantage of cells overexpressing a dyskerin splice variant undergoing a dynamic intracellular trafficking, we were able to show that H/ACA snoRNP components can participate in SG formation, this way contributing to the stress response and perhaps transducing signals from the nucleus to the cytoplasm. Collectively, our results show for the first time that H/ACA snoRNP proteins can have additional non-nuclear functions, either independently or interacting with each other, thus further strengthening the close relationship linking nucleolus to SG composition., (Copyright © 2019 Elsevier B.V. All rights reserved.)
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- 2019
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41. Macrophage Migration Inhibitory Factor Is a Molecular Determinant of the Anti-EGFR Monoclonal Antibody Cetuximab Resistance in Human Colorectal Cancer Cells.
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Russo R, Matrone N, Belli V, Ciardiello D, Valletta M, Esposito S, Pedone PV, Ciardiello F, Troiani T, and Chambery A
- Abstract
Background: The clinical impact of the monoclonal antibody cetuximab targeting the EGFR in colorectal cancer (CRC) is widely recognized. Nevertheless, the onset of cetuximab resistance is a serious issue that limits the effectiveness of this drug in targeted therapies. Unraveling the molecular players involved in cancer resistance is the first step towards the identification of alternative signaling pathways that can be targeted to circumvent resistance mechanisms restoring the efficacy of therapeutic treatments in a tailored manner., Methods: By applying a nanoLC-MS/MS TMT isobaric labeling-based approach, we have delineated a molecular hallmark of cetuximab-resistance in CRC., Results: We identified macrophage migration inhibitory factor (MIF) as a molecular determinant capable of triggering cancer resistance in sensitive human CRC cells. Blocking the MIF axis in resistant cells by a selective MIF inhibitor restores cell sensitivity to cetuximab. The combined treatment with cetuximab and the MIF inhibitor further enhanced cell growth inhibition in CRC resistant cell lines with a synergistic effect depending on inhibition of key downstream effectors of the MAPK and AKT signaling pathways., Conclusions: Collectively, our results suggest the association of MIF signaling and its dysregulation to cetuximab drug resistance, paving the way to the development of personalized combination therapies targeting the MIF axis.
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- 2019
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42. Combined blockade of MEK and PI3KCA as an effective antitumor strategy in HER2 gene amplified human colorectal cancer models.
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Belli V, Matrone N, Napolitano S, Migliardi G, Cottino F, Bertotti A, Trusolino L, Martinelli E, Morgillo F, Ciardiello D, De Falco V, Giunta EF, Bracale U, Ciardiello F, and Troiani T
- Subjects
- Animals, Antineoplastic Agents pharmacology, Biomarkers, Tumor, Cell Line, Tumor, Colorectal Neoplasms drug therapy, Colorectal Neoplasms pathology, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Resistance, Neoplasm drug effects, Drug Resistance, Neoplasm genetics, Female, Humans, MAP Kinase Kinase Kinases metabolism, Mice, Nuclear Proteins metabolism, Transcription Factors metabolism, Xenograft Model Antitumor Assays, Colorectal Neoplasms genetics, Colorectal Neoplasms metabolism, Gene Amplification, MAP Kinase Kinase Kinases antagonists & inhibitors, Nuclear Proteins antagonists & inhibitors, Protein Kinase Inhibitors pharmacology, Receptor, ErbB-2 genetics, Transcription Factors antagonists & inhibitors
- Abstract
Background: Targeting the epidermal growth factor receptor (EGFR) either alone or in combination with chemotherapy is an effective treatment for patients with RAS wild-type metastatic colorectal cancer (mCRC). However, only a small percentage of mCRC patients receive clinical benefits from anti-EGFR therapies, due to the development of resistance mechanisms. In this regard, HER2 has emerged as an actionable target in the treatment of mCRC patients with resistance to anti-EGFR therapy., Methods: We have used SW48 and LIM1215 human colon cancer cell lines, quadruple wild-type for KRAS, NRAS, BRAF and PI3KCA genes, and their HER2-amplified (LIM1215-HER2 and SW48-HER2) derived cells to perform in vitro and in vivo studies in order to identify novel therapeutic strategies in HER2 gene amplified human colorectal cancer., Results: LIM1215-HER2 and SW48-HER2 cells showed over-expression and activation of the HER family receptors and concomitant intracellular downstream signaling including the pro-survival PI3KCA/AKT and the mitogenic RAS/RAF/MEK/MAPK pathways. HER2-amplified cells were treated with several agents including anti-EGFR antibodies (cetuximab, SYM004 and MM151); anti-HER2 (trastuzumab, pertuzumab and lapatinib) inhibitors; anti-HER3 (duligotuzumab) inhibitors; and MEK and PI3KCA inhibitors, such as refametinib and pictilisib, as single agents and in combination. Subsequently, different in vivo experiments have been performed. MEK plus PI3KCA inhibitors treatment determined the best antitumor activity. These results were validated in vivo in HER2-amplified patient derived tumor xenografts from three metastatic colorectal cancer patients., Conclusions: These results suggest that combined therapy with MEK and PI3KCA inhibitors could represent a novel and effective treatment option for HER2-amplified colorectal cancer.
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- 2019
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43. EPHA2 Is a Predictive Biomarker of Resistance and a Potential Therapeutic Target for Improving Antiepidermal Growth Factor Receptor Therapy in Colorectal Cancer.
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Martini G, Cardone C, Vitiello PP, Belli V, Napolitano S, Troiani T, Ciardiello D, Della Corte CM, Morgillo F, Matrone N, Sforza V, Papaccio G, Desiderio V, Paul MC, Moreno-Viedma V, Normanno N, Rachiglio AM, Tirino V, Maiello E, Latiano TP, Rizzi D, Signoriello G, Sibilia M, Ciardiello F, and Martinelli E
- Subjects
- Adult, Aged, Aged, 80 and over, Animals, Antineoplastic Agents, Immunological administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Apoptosis drug effects, Benzamides pharmacology, Biomarkers, Tumor metabolism, Camptothecin analogs & derivatives, Camptothecin therapeutic use, Cell Cycle Checkpoints drug effects, Cell Line, Tumor, Cetuximab administration & dosage, Colorectal Neoplasms pathology, Ephrin-A2 antagonists & inhibitors, ErbB Receptors antagonists & inhibitors, Female, Fluorouracil therapeutic use, Humans, Leucovorin therapeutic use, Male, Mice, Mice, Inbred BALB C, Mice, Nude, Middle Aged, Niacinamide analogs & derivatives, Niacinamide pharmacology, Progression-Free Survival, RNA Interference, Receptor, EphA2, Signal Transduction drug effects, Transfection, Xenograft Model Antitumor Assays, Antineoplastic Agents, Immunological pharmacology, Antineoplastic Agents, Immunological therapeutic use, Cetuximab pharmacology, Cetuximab therapeutic use, Colorectal Neoplasms drug therapy, Drug Resistance, Neoplasm, Ephrin-A2 metabolism
- Abstract
The EPHA2 tyrosine kinase receptor is implicated in tumor progression and targeted therapies resistance. We evaluated EPHA2 as a potential resistance marker to the antiepidermal growth factor receptor (EGFR) monoclonal antibody cetuximab in colorectal cancer. We studied activation of EPHA2 in a panel of human colorectal cancer cell lines sensitive or resistant to anti-EGFR drugs. The in vitro and in vivo effects of ALW-II-41-27 (an EPHA2 inhibitor) and/or cetuximab treatment were tested. Formalin-fixed paraffin-embedded tumor specimens from 82 RAS wild-type (WT) metastatic colorectal cancer patients treated with FOLFIRI + cetuximab as first-line therapy in the CAPRI-GOIM trial were assessed for EPHA2 expression by immunohistochemistry and correlated with treatment efficacy. EPHA2 was differentially activated in colorectal cancer cell lines. Combined treatment with ALW-II-41-27 plus cetuximab reverted primary and acquired resistance to cetuximab, causing cell growth inhibition, inducing apoptosis and cell-cycle G1-G2 arrest. In tumor xenograft models, upon progression to cetuximab, ALW-II-41-27 addition significantly inhibited tumor growth. EPHA2 protein expression was detected in 55 of 82 tumor samples, frequently expressed in less-differentiated and left-sided tumors. High levels of EPHA2 significantly correlated with worse progression-free survival [8.6 months; confidence interval (CI) 95%, 6.4-10.8; vs. 12.3 months; CI 95%, 10.4-14.2; P = 0.03] and with increased progression rate (29% vs. 9%, P = 0.02). A specific EPHA2 inhibitor reverts in vitro and in vivo primary and acquired resistance to anti-EGFR therapy. EPHA2 levels are significantly associated with worse outcome in patients treated with FOLFIRI + cetuximab. These results highlight EPHA2 as a potential therapeutic target in metastatic colorectal cancer., (©2019 American Association for Cancer Research.)
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- 2019
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44. Receptor tyrosine kinase-dependent PI3K activation is an escape mechanism to vertical suppression of the EGFR/RAS/MAPK pathway in KRAS-mutated human colorectal cancer cell lines.
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Vitiello PP, Cardone C, Martini G, Ciardiello D, Belli V, Matrone N, Barra G, Napolitano S, Della Corte C, Turano M, Furia M, Troiani T, Morgillo F, De Vita F, Ciardiello F, and Martinelli E
- Subjects
- Apoptosis, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Cell Movement, Cell Proliferation, Colorectal Neoplasms drug therapy, Colorectal Neoplasms metabolism, Drug Resistance, Neoplasm genetics, ErbB Receptors genetics, Humans, Phosphatidylinositol 3-Kinases genetics, Phosphorylation, Protein Kinase Inhibitors pharmacology, Tumor Cells, Cultured, Colorectal Neoplasms pathology, ErbB Receptors metabolism, MAP Kinase Signaling System drug effects, Mutation, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins p21(ras) genetics
- Abstract
Background: Previous studies showed that the combination of an anti-Epidermal growth factor (EGFR) and a MEK-inhibitor is able to prevent the onset of resistance to anti-EGFR monoclonal antibodies in KRAS-wild type colorectal cancer (CRC), while the same combination reverts anti-EGFR primary resistance in KRAS mutated CRC cell lines. However, rapid onset of resistance is a limit to combination therapies in KRAS mutated CRC., Methods: We generated four different KRAS mutated CRC cell lines resistant to a combination of cetuximab (an anti-EGFR antibody) and refametinib (a selective MEK-inhibitor) after continuous exposure to increasing concentration of the drugs. We characterized these resistant cell lines by evaluating the expression and activation status of a panel of receptor tyrosine kinases (RTKs) and intracellular transducers by immunoblot and qRT-PCR. Oncomine comprehensive assay and microarray analysis were carried out to investigate new acquired mutations or transcriptomic adaptation, respectively, in the resistant cell lines. Immunofluorescence assay was used to show the localization of RTKs in resistant and parental clones., Results: We found that PI3K-AKT pathway activation acts as an escape mechanism in cell lines with acquired resistance to combined inhibition of EGFR and MEK. AKT pathway activation is coupled to the activation of multiple RTKs such as HER2, HER3 and IGF1R, though its pharmacological inhibition is not sufficient to revert the resistant phenotype. PI3K pathway activation is mediated by autocrine loops and by heterodimerization of multiple receptors., Conclusions: PI3K activation plays a central role in the acquired resistance to the combination of anti-EGFR and MEK-inhibitor in KRAS mutated colorectal cancer cell lines. PI3K activation is cooperatively achieved through the activation of multiple RTKs such as HER2, HER3 and IGF1R.
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- 2019
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45. A functional connection between dyskerin and energy metabolism.
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Angrisani A, Matrone N, Belli V, Vicidomini R, Di Maio N, Turano M, Scialò F, Netti PA, Porcellini A, and Furia M
- Subjects
- HeLa Cells, Humans, Mitochondria metabolism, Protein Isoforms metabolism, Reactive Oxygen Species metabolism, Signal Transduction, Superoxides metabolism, Cell Cycle Proteins metabolism, Energy Metabolism, Nuclear Proteins metabolism
- Abstract
The human DKC1 gene encodes dyskerin, an evolutionarily conserved nuclear protein whose overexpression represents a common trait of many types of aggressive sporadic cancers. As a crucial component of the nuclear H/ACA snoRNP complexes, dyskerin is involved in a variety of essential processes, including telomere maintenance, splicing efficiency, ribosome biogenesis, snoRNAs stabilization and stress response. Although multiple minor dyskerin splicing isoforms have been identified, their functions remain to be defined. Considering that low-abundance splice variants could contribute to the wide functional repertoire attributed to dyskerin, possibly having more specialized tasks or playing significant roles in changing cell status, we investigated in more detail the biological roles of a truncated dyskerin isoform that lacks the C-terminal nuclear localization signal and shows a prevalent cytoplasmic localization. Here we show that this dyskerin variant can boost energy metabolism and improve respiration, ultimately conferring a ROS adaptive response and a growth advantage to cells. These results reveal an unexpected involvement of DKC1 in energy metabolism, highlighting a previously underscored role in the regulation of metabolic cell homeostasis., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2018
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46. Regorafenib in combination with silybin as a novel potential strategy for the treatment of metastatic colorectal cancer.
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Belli V, Sforza V, Cardone C, Martinelli E, Barra G, Matrone N, Napolitano S, Morgillo F, Tuccillo C, Federico A, Dallio M, Loguercio C, Gravina AG, De Palma R, Ciardiello F, and Troiani T
- Abstract
Purpose: Regorafenib, an oral multikinase inhibitor, has demonstrated survival benefit in metastatic colorectal cancer (mCRC) patients that have progressed after all standard therapies. However, novel strategies to improve tolerability and enhance anti-cancer efficacy are needed., Experimental Design: We have evaluated in vitro the effects of regorafenib in combination with silybin, a biologically active component extracted from the seeds of Silybum marianum, in a panel of human colon cancer cells. Furthermore, we have prospectively treated a cohort of 22 refractory mCRC patients with regorafenib plus silybin., Results: Treatment with regorafenib determined a dose-dependent growth inhibition whereas treatment with silybin had no anti-proliferative effects among all cancer cells tested. The combined treatment with regorafenib and silybin induced synergistic anti-proliferative and apoptotic effects by blocking PI3K/AKT/mTOR intracellular pathway. Moreover, combined treatment with regorafenib and silybin increased the production of reactive oxygen species levels within cells. In an exploratory proof of concept clinical study in a cohort of 22 mCRC patients after failure of all standard therapies, the clinical activity of regorafenib in combination with silybin was assessed. A median progression-free survival of 10.0 months and a median overall survival of 17.6 months were observed in these patients. These results suggest that the combined treatment potentially increases the clinical efficacy of regorafenib. Moreover, due to its anti-oxidative properties, silybin could protect patients from drug-induced liver damages, allowing to continue an effective anti-cancer therapy., Conclusions: The present study suggests that silybin in combination with regorafenib is a promising strategy for treatment of metastatic colorectal patients., Competing Interests: CONFLICTS OF INTEREST Authors have no conflicts of interest to disclose.
- Published
- 2017
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47. Antitumor efficacy of triple monoclonal antibody inhibition of epidermal growth factor receptor (EGFR) with MM151 in EGFR-dependent and in cetuximab-resistant human colorectal cancer cells.
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Napolitano S, Martini G, Martinelli E, Della Corte CM, Morgillo F, Belli V, Cardone C, Matrone N, Ciardiello F, and Troiani T
- Abstract
Purpose: We investigated the effect of triple monoclonal antibody inhibition of EGFR to overcome acquired resistance to first generation of anti-EGFR inhibitors., Experimental Design: MM151 is a mixture of three different monoclonal IgG1 antibodies directed toward three different, non-overlapping, epitopes of the EGFR. We performed an in vivo study by using human CRC cell lines (SW48, LIM 1215 and CACO2) which are sensitive to EGFR inhibitors, in order to evaluate the activity of MM151 as compared to standard anti-EGFR mAbs, such as cetuximab, as single agent or in a sequential strategy of combination MM151 with irinotecan (induction therapy) followed by MM151 with a selective MEK1/2 inhibitor (MEKi) (maintenance therapy). Furthermore, the ability of MM151 to overcome acquired resistance to cetuximab has been also evaluated in cetuximab-refractory CRC models., Results: MM151 shown stronger antitumor activity as compared to cetuximab. The maintenance treatment with MM151 plus MEKi resulted the most effective therapeutic modality. In fact, this combination caused an almost complete suppression of tumor growth in SW48, LIM 1215 and CACO2 xenografts model at 30 week. Moreover, in this treatment group, mice with no evidence of tumor were more than double as compared to single agent treated mice. Its superior activity has also been demonstrated, in cetuximab-refractory CRC models., Conclusions: These results provide experimental evidence that more efficient and complete EGFR blockade may determine better antitumor activity and could contribute to prevent and/or overcome acquired resistance to EGFR inhibitors., Competing Interests: CONFLICTS OF INTEREST All coauthors have no conflicts of interest.
- Published
- 2017
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