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1. Endothelin-1–Mediated Drug Resistance in EGFR-Mutant Non-Small Cell Lung Carcinoma

Author

Pulido, Inés, Ollosi, Stephen, Aparisi, Salvador, Becker, Jeffrey H, Aliena-Valero, Alicia, Benet, Marta, Rodríguez, María L, López, Adrián, Tamayo-Torres, Eva, Chuliá-Peris, Lourdes, García-Cañaveras, Juan Carlos, Soucheray, Margaret, Dalheim, Annika V, Salom, Juan B, Qiu, Wei, Kaja, Simon, Fernández-Coronado, Javier Alcácer, Alandes, Sandra, Alcácer, Javier, Al-Shahrour, Fátima, Borgia, Jeffrey A, Juan, Oscar, Nishimura, Michael I, Lahoz, Agustín, Carretero, Julián, and Shimamura, Takeshi

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Immunology, Lung, Lung Cancer, Cancer, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Animals, Antineoplastic Agents, Biological Availability, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Drug Resistance, Neoplasm, Endothelin-1, ErbB Receptors, Erlotinib Hydrochloride, Gefitinib, Humans, Lung Neoplasms, Mice, Mutation, Protein Kinase Inhibitors, Vascular Endothelial Growth Factor A, Vasoconstriction, Xenograft Model Antitumor Assays, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Progression on therapy in non-small cell lung carcinoma (NSCLC) is often evaluated radiographically, however, image-based evaluation of said therapies may not distinguish disease progression due to intrinsic tumor drug resistance or inefficient tumor penetration of the drugs. Here we report that the inhibition of mutated EGFR promotes the secretion of a potent vasoconstrictor, endothelin-1 (EDN1), which continues to increase as the cells become resistant with a mesenchymal phenotype. As EDN1 and its receptor (EDNR) is linked to cancer progression, EDNR-antagonists have been evaluated in several clinical trials with disappointing results. These trials were based on a hypothesis that the EDN1-EDNR axis activates the MAPK-ERK signaling pathway that is vital to the cancer cell survival; the trials were not designed to evaluate the impact of tumor-derived EDN1 in modifying tumor microenvironment or contributing to drug resistance. Ectopic overexpression of EDN1 in cells with mutated EGFR resulted in poor drug delivery and retarded growth in vivo but not in vitro. Intratumoral injection of recombinant EDN significantly reduced blood flow and subsequent gefitinib accumulation in xenografted EGFR-mutant tumors. Furthermore, depletion of EDN1 or the use of endothelin receptor inhibitors bosentan and ambrisentan improved drug penetration into tumors and restored blood flow in tumor-associated vasculature. Correlatively, these results describe a simplistic endogenous yet previously unrealized resistance mechanism inherent to a subset of EGFR-mutant NSCLC to attenuate tyrosine kinase inhibitor delivery to the tumors by limiting drug-carrying blood flow and the drug concentration in tumors. SIGNIFICANCE: EDNR antagonists can be repurposed to improve drug delivery in VEGFA-secreting tumors, which normally respond to TKI treatment by secreting EDN1, promoting vasoconstriction, and limiting blood and drug delivery.

Published
2020

2. CXCR7 Reactivates ERK Signaling to Promote Resistance to EGFR Kinase Inhibitors in NSCLC

Author

Becker, Jeffrey H, Gao, Yandi, Soucheray, Margaret, Pulido, Ines, Kikuchi, Eiki, Rodríguez, María L, Gandhi, Rutu, Lafuente-Sanchis, Aranzazu, Aupí, Miguel, Alcácer Fernández-Coronado, Javier, Martín-Martorell, Paloma, Cremades, Antonio, Galbis-Caravajal, José M, Alcácer, Javier, Christensen, Camilla L, Simms, Patricia, Hess, Ashley, Asahina, Hajime, Kahle, Michael P, Al-Shahrour, Fatima, Borgia, Jeffrey A, Lahoz, Agustín, Insa, Amelia, Juan, Oscar, Jänne, Pasi A, Wong, Kwok-Kin, Carretero, Julian, and Shimamura, Takeshi

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Lung Cancer, Cancer, Lung, Clinical Research, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Animals, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Drug Resistance, Neoplasm, Epithelial-Mesenchymal Transition, ErbB Receptors, Humans, Lung Neoplasms, MAP Kinase Signaling System, Mice, Transgenic, Mutation, Neoplasms, Experimental, Protein Kinase Inhibitors, Receptors, CXCR, beta-Arrestins, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Although EGFR mutant-selective tyrosine kinase inhibitors (TKI) are clinically effective, acquired resistance can occur by reactivating ERK. We show using in vitro models of acquired EGFR TKI resistance with a mesenchymal phenotype that CXCR7, an atypical G protein-coupled receptor, activates the MAPK-ERK pathway via β-arrestin. Depletion of CXCR7 inhibited the MAPK pathway, significantly attenuated EGFR TKI resistance, and resulted in mesenchymal-to-epithelial transition. CXCR7 overexpression was essential in reactivation of ERK1/2 for the generation of EGFR TKI-resistant persister cells. Many patients with non-small cell lung cancer (NSCLC) harboring an EGFR kinase domain mutation, who progressed on EGFR inhibitors, demonstrated increased CXCR7 expression. These data suggest that CXCR7 inhibition could considerably delay and prevent the emergence of acquired EGFR TKI resistance in EGFR-mutant NSCLC. SIGNIFICANCE: Increased expression of the chemokine receptor CXCR7 constitutes a mechanism of resistance to EGFR TKI in patients with non-small cell lung cancer through reactivation of ERK signaling.

Published
2019

4. Data from CXCR7 Reactivates ERK Signaling to Promote Resistance to EGFR Kinase Inhibitors in NSCLC

Author

Becker, Jeffrey H., primary, Gao, Yandi, primary, Soucheray, Margaret, primary, Pulido, Ines, primary, Kikuchi, Eiki, primary, Rodríguez, María L., primary, Gandhi, Rutu, primary, Lafuente-Sanchis, Aranzazu, primary, Aupí, Miguel, primary, Alcácer Fernández-Coronado, Javier, primary, Martín-Martorell, Paloma, primary, Cremades, Antonio, primary, Galbis-Caravajal, José M., primary, Alcácer, Javier, primary, Christensen, Camilla L., primary, Simms, Patricia, primary, Hess, Ashley, primary, Asahina, Hajime, primary, Kahle, Michael P., primary, Al-Shahrour, Fatima, primary, Borgia, Jeffrey A., primary, Lahoz, Agustín, primary, Insa, Amelia, primary, Juan, Oscar, primary, Jänne, Pasi A., primary, Wong, Kwok-Kin, primary, Carretero, Julian, primary, and Shimamura, Takeshi, primary

Published
2023
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5. Supplementary Figure S1-S5 from Endothelin-1–Mediated Drug Resistance in EGFR-Mutant Non-Small Cell Lung Carcinoma

Author

Pulido, Inés, primary, Ollosi, Stephen, primary, Aparisi, Salvador, primary, Becker, Jeffrey H., primary, Aliena-Valero, Alicia, primary, Benet, Marta, primary, Rodríguez, María L., primary, López, Adrián, primary, Tamayo-Torres, Eva, primary, Chuliá-Peris, Lourdes, primary, García-Cañaveras, Juan Carlos, primary, Soucheray, Margaret, primary, Dalheim, Annika V., primary, Salom, Juan B., primary, Qiu, Wei, primary, Kaja, Simon, primary, Fernández-Coronado, Javier Alcácer, primary, Alandes, Sandra, primary, Alcácer, Javier, primary, Al-Shahrour, Fátima, primary, Borgia, Jeffrey A., primary, Juan, Oscar, primary, Nishimura, Michael I., primary, Lahoz, Agustín, primary, Carretero, Julián, primary, and Shimamura, Takeshi, primary

Published
2023
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6. Supplementary Table 1 from CXCR7 Reactivates ERK Signaling to Promote Resistance to EGFR Kinase Inhibitors in NSCLC

Author

Becker, Jeffrey H., primary, Gao, Yandi, primary, Soucheray, Margaret, primary, Pulido, Ines, primary, Kikuchi, Eiki, primary, Rodríguez, María L., primary, Gandhi, Rutu, primary, Lafuente-Sanchis, Aranzazu, primary, Aupí, Miguel, primary, Alcácer Fernández-Coronado, Javier, primary, Martín-Martorell, Paloma, primary, Cremades, Antonio, primary, Galbis-Caravajal, José M., primary, Alcácer, Javier, primary, Christensen, Camilla L., primary, Simms, Patricia, primary, Hess, Ashley, primary, Asahina, Hajime, primary, Kahle, Michael P., primary, Al-Shahrour, Fatima, primary, Borgia, Jeffrey A., primary, Lahoz, Agustín, primary, Insa, Amelia, primary, Juan, Oscar, primary, Jänne, Pasi A., primary, Wong, Kwok-Kin, primary, Carretero, Julian, primary, and Shimamura, Takeshi, primary

Published
2023
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7. Supplementary Materials and Method from CXCR7 Reactivates ERK Signaling to Promote Resistance to EGFR Kinase Inhibitors in NSCLC

Author

Becker, Jeffrey H., primary, Gao, Yandi, primary, Soucheray, Margaret, primary, Pulido, Ines, primary, Kikuchi, Eiki, primary, Rodríguez, María L., primary, Gandhi, Rutu, primary, Lafuente-Sanchis, Aranzazu, primary, Aupí, Miguel, primary, Alcácer Fernández-Coronado, Javier, primary, Martín-Martorell, Paloma, primary, Cremades, Antonio, primary, Galbis-Caravajal, José M., primary, Alcácer, Javier, primary, Christensen, Camilla L., primary, Simms, Patricia, primary, Hess, Ashley, primary, Asahina, Hajime, primary, Kahle, Michael P., primary, Al-Shahrour, Fatima, primary, Borgia, Jeffrey A., primary, Lahoz, Agustín, primary, Insa, Amelia, primary, Juan, Oscar, primary, Jänne, Pasi A., primary, Wong, Kwok-Kin, primary, Carretero, Julian, primary, and Shimamura, Takeshi, primary

Published
2023
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8. Supplementary Figure Legends from CXCR7 Reactivates ERK Signaling to Promote Resistance to EGFR Kinase Inhibitors in NSCLC

Author

Becker, Jeffrey H., primary, Gao, Yandi, primary, Soucheray, Margaret, primary, Pulido, Ines, primary, Kikuchi, Eiki, primary, Rodríguez, María L., primary, Gandhi, Rutu, primary, Lafuente-Sanchis, Aranzazu, primary, Aupí, Miguel, primary, Alcácer Fernández-Coronado, Javier, primary, Martín-Martorell, Paloma, primary, Cremades, Antonio, primary, Galbis-Caravajal, José M., primary, Alcácer, Javier, primary, Christensen, Camilla L., primary, Simms, Patricia, primary, Hess, Ashley, primary, Asahina, Hajime, primary, Kahle, Michael P., primary, Al-Shahrour, Fatima, primary, Borgia, Jeffrey A., primary, Lahoz, Agustín, primary, Insa, Amelia, primary, Juan, Oscar, primary, Jänne, Pasi A., primary, Wong, Kwok-Kin, primary, Carretero, Julian, primary, and Shimamura, Takeshi, primary

Published
2023
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9. Supplementary Figures S1-S6 from CXCR7 Reactivates ERK Signaling to Promote Resistance to EGFR Kinase Inhibitors in NSCLC

Author

Becker, Jeffrey H., primary, Gao, Yandi, primary, Soucheray, Margaret, primary, Pulido, Ines, primary, Kikuchi, Eiki, primary, Rodríguez, María L., primary, Gandhi, Rutu, primary, Lafuente-Sanchis, Aranzazu, primary, Aupí, Miguel, primary, Alcácer Fernández-Coronado, Javier, primary, Martín-Martorell, Paloma, primary, Cremades, Antonio, primary, Galbis-Caravajal, José M., primary, Alcácer, Javier, primary, Christensen, Camilla L., primary, Simms, Patricia, primary, Hess, Ashley, primary, Asahina, Hajime, primary, Kahle, Michael P., primary, Al-Shahrour, Fatima, primary, Borgia, Jeffrey A., primary, Lahoz, Agustín, primary, Insa, Amelia, primary, Juan, Oscar, primary, Jänne, Pasi A., primary, Wong, Kwok-Kin, primary, Carretero, Julian, primary, and Shimamura, Takeshi, primary

Published
2023
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10. Data from Endothelin-1–Mediated Drug Resistance in EGFR-Mutant Non-Small Cell Lung Carcinoma

Author

Pulido, Inés, primary, Ollosi, Stephen, primary, Aparisi, Salvador, primary, Becker, Jeffrey H., primary, Aliena-Valero, Alicia, primary, Benet, Marta, primary, Rodríguez, María L., primary, López, Adrián, primary, Tamayo-Torres, Eva, primary, Chuliá-Peris, Lourdes, primary, García-Cañaveras, Juan Carlos, primary, Soucheray, Margaret, primary, Dalheim, Annika V., primary, Salom, Juan B., primary, Qiu, Wei, primary, Kaja, Simon, primary, Fernández-Coronado, Javier Alcácer, primary, Alandes, Sandra, primary, Alcácer, Javier, primary, Al-Shahrour, Fátima, primary, Borgia, Jeffrey A., primary, Juan, Oscar, primary, Nishimura, Michael I., primary, Lahoz, Agustín, primary, Carretero, Julián, primary, and Shimamura, Takeshi, primary

Published
2023
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11. Supplementary Figure Legend from Endothelin-1–Mediated Drug Resistance in EGFR-Mutant Non-Small Cell Lung Carcinoma

Author

Pulido, Inés, primary, Ollosi, Stephen, primary, Aparisi, Salvador, primary, Becker, Jeffrey H., primary, Aliena-Valero, Alicia, primary, Benet, Marta, primary, Rodríguez, María L., primary, López, Adrián, primary, Tamayo-Torres, Eva, primary, Chuliá-Peris, Lourdes, primary, García-Cañaveras, Juan Carlos, primary, Soucheray, Margaret, primary, Dalheim, Annika V., primary, Salom, Juan B., primary, Qiu, Wei, primary, Kaja, Simon, primary, Fernández-Coronado, Javier Alcácer, primary, Alandes, Sandra, primary, Alcácer, Javier, primary, Al-Shahrour, Fátima, primary, Borgia, Jeffrey A., primary, Juan, Oscar, primary, Nishimura, Michael I., primary, Lahoz, Agustín, primary, Carretero, Julián, primary, and Shimamura, Takeshi, primary

Published
2023
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12. Supplementary Materials and Methods from Endothelin-1–Mediated Drug Resistance in EGFR-Mutant Non-Small Cell Lung Carcinoma

Author

Pulido, Inés, primary, Ollosi, Stephen, primary, Aparisi, Salvador, primary, Becker, Jeffrey H., primary, Aliena-Valero, Alicia, primary, Benet, Marta, primary, Rodríguez, María L., primary, López, Adrián, primary, Tamayo-Torres, Eva, primary, Chuliá-Peris, Lourdes, primary, García-Cañaveras, Juan Carlos, primary, Soucheray, Margaret, primary, Dalheim, Annika V., primary, Salom, Juan B., primary, Qiu, Wei, primary, Kaja, Simon, primary, Fernández-Coronado, Javier Alcácer, primary, Alandes, Sandra, primary, Alcácer, Javier, primary, Al-Shahrour, Fátima, primary, Borgia, Jeffrey A., primary, Juan, Oscar, primary, Nishimura, Michael I., primary, Lahoz, Agustín, primary, Carretero, Julián, primary, and Shimamura, Takeshi, primary

Published
2023
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14. Endothelin-1-mediated Drug Resistance in EGFR-mutant NSCLC

Author

Pulido, Inés, Ollosi, Stephen, Aparisi, Salvador, Becker, Jeffrey H., Aliena-Valero, Alicia, Benet, Marta, Rodríguez, María L., López, Adrián, Tamayo-Torres, Eva, Chuliá-Peris, Lourdes, García-Cañaveras, Juan Carlos, Soucheray, Margaret, Dalheim, Annika V., Salom, Juan B., Qiu, Wei, Kaja, Simon, Fernández-Coronado, Javier Alcácer, Alandes, Sandra, Alcácer, Javier, Al-Shahrour, Fátima, Borgia, Jeffrey A., Juan, Oscar, Nishimura, Michael I., Lahoz, Agustín, Carretero, Julián, and Shimamura, Takeshi

Subjects
Vascular Endothelial Growth Factor A, Lung Neoplasms, Endothelin-1, Biological Availability, Antineoplastic Agents, Gefitinib, Xenograft Model Antitumor Assays, Article, ErbB Receptors, Erlotinib Hydrochloride, Mice, Drug Resistance, Neoplasm, Vasoconstriction, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Mutation, Animals, Humans, Protein Kinase Inhibitors
Abstract

Progression on therapy in NSCLC is often evaluated radiographically; however, image-based evaluation of said therapies may not distinguish disease progression due to intrinsic tumor drug resistance or inefficient tumor penetration of the drugs. Here we report that the inhibition of mutated EGFR promotes the secretion of a potent vasoconstrictor, endothelin-1 (EDN1), which continues to increase as the cells become resistant with a mesenchymal phenotype. As EDN1 and its receptor (EDNR) is linked to cancer progression, EDNR-antagonists have been evaluated in several clinical trials with disappointing results. These trials were based on a hypothesis that the EDN1-EDNR axis activates the MAPK-ERK signaling pathway that is vital to the cancer cell survival; the trials were not designed to evaluate the impact of tumor-derived EDN1 in modifying tumor microenvironment or contributing to drug resistance. Ectopic overexpression of EDN1 in cells with mutated EGFR resulted in poor drug delivery and retarded growth in vivo but not in vitro. Intratumoral injection of rEDN significantly reduced blood flow and subsequent gefitinib accumulation in xenografted EGFR mutant tumors. Furthermore, depletion of EDN1 or the use of endothelin receptor inhibitors bosentan and ambrisentan improved drug penetration into tumors and restored blood flow in tumor-associated vasculature. Correlatively, these results describe a simplistic endogenous yet previously unrealized resistance mechanism inherent to a subset of EGFR-mutant NSCLC to attenuate TKI delivery to the tumors by limiting drug-carrying blood flow and the drug concentration in tumors.

Published
2020

15. Nicotinamide Riboside and Pterostilbene Cooperatively Delay Motor Neuron Failure in ALS SOD1G93A Mice

Author

Obrador, Elena, primary, Salvador, Rosario, additional, Marchio, Patricia, additional, López-Blanch, Rafael, additional, Jihad-Jebbar, Ali, additional, Rivera, Pilar, additional, Vallés, Soraya L., additional, Banacloche, Salvador, additional, Alcácer, Javier, additional, Colomer, Nuria, additional, Coronado, Javier A., additional, Alandes, Sandra, additional, Drehmer, Eraci, additional, Benlloch, María, additional, and Estrela, José M., additional

Published
2020
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16. Selective targeting of collagen IV in the cancer cell microenvironment reduces tumor burden

Author

Revert, Fernando, primary, Revert-Ros, Francisco, additional, Blasco, Raül, additional, Artigot, Aida, additional, López-Pascual, Ernesto, additional, Gozalbo-Rovira, Roberto, additional, Ventura, Ignacio, additional, Gutiérrez-Carbonell, Elain, additional, Roda, Nuria, additional, Ruíz-Sanchis, Daniel, additional, Forteza, Jerónimo, additional, Alcácer, Javier, additional, Pérez-Sastre, Alejandra, additional, Díaz, Ana, additional, Pérez-Payá, Enrique, additional, Sanz-Cervera, Juan F., additional, and Saus, Juan, additional

Published
2018
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17. Pterostilbene Decreases the Antioxidant Defenses of Aggressive Cancer Cells In Vivo: A Physiological Glucocorticoids- and Nrf2-Dependent Mechanism

Author

Benlloch, María, primary, Obrador, Elena, additional, Valles, Soraya L., additional, Rodriguez, María L., additional, Sirerol, J. Antoni, additional, Alcácer, Javier, additional, Pellicer, José A., additional, Salvador, Rosario, additional, Cerdá, Concha, additional, Sáez, Guillermo T., additional, and Estrela, José M., additional

Published
2016
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18. Glucocorticoid Receptor Knockdown Decreases the Antioxidant Protection of B16 Melanoma Cells: An Endocrine System-Related Mechanism that Compromises Metastatic Cell Resistance to Vascular Endothelium-Induced Tumor Cytotoxicity

Author

Obrador, Elena, primary, Valles, Soraya L., additional, Benlloch, María, additional, Sirerol, J. Antoni, additional, Pellicer, José A., additional, Alcácer, Javier, additional, Coronado, Javier Alcácer-F., additional, and Estrela, José M., additional

Published
2014
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19. Increased Goodpasture Antigen-Binding Protein Expression Induces Type IV Collagen Disorganization and Deposit of Immunoglobulin A in Glomerular Basement Membrane

Author

Revert, Fernando, primary, Merino, Ramón, additional, Monteagudo, Carlos, additional, Macias, Jesús, additional, Peydró, Amando, additional, Alcácer, Javier, additional, Muniesa, Pedro, additional, Marquina, Regina, additional, Blanco, Mario, additional, Iglesias, Marcos, additional, Revert-Ros, Francisco, additional, Merino, Jesús, additional, and Saus, Juan, additional

Published
2007
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20. Glucocorticoid receptor antagonism overcomes resistance to BRAF inhibition in BRAF V600E -mutated metastatic melanoma.

Author

Estrela JM, Salvador R, Marchio P, Valles SL, López-Blanch R, Rivera P, Benlloch M, Alcácer J, Pérez CL, Pellicer JA, and Obrador E

Abstract

Clinical applications of glucocorticoids (GC) in Oncology are dependent on their pro-apoptotic action to treat lymphoproliferative cancers, and to alleviate side effects induced by chemotherapy and/or radiotherapy. However, the mechanism(s) by which GC may also promote tumor progression remains unclear. GC receptor (GR) knockdown decreases the antioxidant protection of highly metastatic B16-F10 melanoma cells. We hypothesize that a GR antagonist (RU486, mifepristone) could increase the efficacy of BRAF-related therapy in BRAF V600E -mutated metastatic melanoma. In vivo formed spontaneous skin tumors were reinoculated into nude mice to expand the metastases of different human BRAF V600E melanoma cells. The GR content of melanoma cell lines was measured by [ 3 H]-labeled ligand binding assay. Nuclear Nrf2 and its transcription activity was investigated by RT-PCR, western blotting, and by measuring Nrf2- and redox state-related enzyme activities and metabolites. GR knockdown was achieved using lentivirus, and GR overexpression by transfection with the NR3C1 plasmid. shRNA-induced selective Bcl-xL, Mcl-1, AKT1 or NF-κB/p65 depletion was used to test the efficacy of vemurafenib (VMF) and RU486 against BRAF V600E -mutated metastatic melanoma. During early progression of skin melanoma metastases, RU486 and VMF induced a drastic metastases regression. However, treatment at an advanced stage of growth demonstrated the development of resistance to RU486 and VMF. This resistance was mechanistically linked to overexpression of specific proteins of the Bcl-2 family (Bcl-xL and Mcl-1 in our experimental models). We found that melanoma resistance is decreased if AKT and NF-κB signaling pathways are blocked. Our results highlight mechanisms by which metastatic melanoma cells adapt to survive., Competing Interests: None., (AJCR Copyright © 2019.)

Published
2019

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