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186 results on '"Brand, Toni M."'

1. Use of nonsteroidal anti-inflammatory drugs predicts improved patient survival for PIK3CA-altered head and neck cancer

Author

Hedberg, Matthew L, Peyser, Noah D, Bauman, Julie E, Gooding, William E, Li, Hua, Bhola, Neil E, Zhu, Tian Ran, Zeng, Yan, Brand, Toni M, Kim, Mi-Ok, Jordan, Richard CK, VandenBerg, Scott, Olivas, Victor, Bivona, Trever G, Chiosea, Simion I, Wang, Lin, Mills, Gordon B, Johnson, Jonas T, Duvvuri, Umamaheswar, Ferris, Robert L, Ha, Patrick, Johnson, Daniel E, and Grandis, Jennifer R

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Dental/Oral and Craniofacial Disease, Cancer, Clinical Research, Orphan Drug, Rare Diseases, Adult, Aged, Animals, Anti-Inflammatory Agents, Non-Steroidal, Carcinoma, Squamous Cell, Class I Phosphatidylinositol 3-Kinases, Disease-Free Survival, Female, Head and Neck Neoplasms, Humans, Male, Mice, Mice, Inbred NOD, Middle Aged, Mutation, Neoplasm Proteins, Survival Rate, Xenograft Model Antitumor Assays, Medical and Health Sciences, Immunology, Biomedical and clinical sciences, Health sciences
Abstract

PIK3CA is the most commonly altered oncogene in head and neck squamous cell carcinoma (HNSCC). We evaluated the impact of nonsteroidal anti-inflammatory drugs (NSAIDs) on survival in a PIK3CA-characterized cohort of 266 HNSCC patients and explored the mechanism in relevant preclinical models including patient-derived xenografts. Among subjects with PIK3CA mutations or amplification, regular NSAID use (≥6 mo) conferred markedly prolonged disease-specific survival (DSS; hazard ratio 0.23, P = 0.0032, 95% CI 0.09-0.62) and overall survival (OS; hazard ratio 0.31, P = 0.0043, 95% CI 0.14-0.69) compared with nonregular NSAID users. For PIK3CA-altered HNSCC, predicted 5-yr DSS was 72% for NSAID users and 25% for nonusers; predicted 5-yr OS was 78% for regular NSAID users and 45% for nonregular users. PIK3CA mutation predicted sensitivity to NSAIDs in preclinical models in association with increased systemic PGE2 production. These findings uncover a biologically plausible rationale to implement NSAID therapy in PIK3CA-altered HNSCC.

Published
2019

2. Multiple Routes to Oncogenesis Are Promoted by the Human Papillomavirus-Host Protein Network.

Author

Eckhardt, Manon, Zhang, Wei, Gross, Andrew M, Von Dollen, John, Johnson, Jeffrey R, Franks-Skiba, Kathleen E, Swaney, Danielle L, Johnson, Tasha L, Jang, Gwendolyn M, Shah, Priya S, Brand, Toni M, Archambault, Jacques, Kreisberg, Jason F, Grandis, Jennifer R, Ideker, Trey, and Krogan, Nevan J

Abstract

We have mapped a global network of virus-host protein interactions by purification of the complete set of human papillomavirus (HPV) proteins in multiple cell lines followed by mass spectrometry analysis. Integration of this map with tumor genome atlases shows that the virus targets human proteins frequently mutated in HPV- but not HPV+ cancers, providing a unique opportunity to identify novel oncogenic events phenocopied by HPV infection. For example, we find that the NRF2 transcriptional pathway, which protects against oxidative stress, is activated by interaction of the NRF2 regulator KEAP1 with the viral protein E1. We also demonstrate that the L2 HPV protein physically interacts with the RNF20/40 histone ubiquitination complex and promotes tumor cell invasion in an RNF20/40-dependent manner. This combined proteomic and genetic approach provides a systematic means to study the cellular mechanisms hijacked by virally induced cancers.Significance: In this study, we created a protein-protein interaction network between HPV and human proteins. An integrative analysis of this network and 800 tumor mutation profiles identifies multiple oncogenesis pathways promoted by HPV interactions that phenocopy recurrent mutations in cancer, yielding an expanded definition of HPV oncogenic roles. Cancer Discov; 8(11); 1474-89. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 1333.

Published
2018

3. BET inhibition overcomes receptor tyrosine kinase-mediated cetuximab resistance in HNSCC

Author

Leonard, Brandon, Brand, Toni M, O'Keefe, Rachel A, Lee, Eliot D, Zeng, Yan, Kemmer, Jacquelyn D, Li, Hua, Grandis, Jennifer R, and Bhola, Neil E

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Genetics, Cancer, Orphan Drug, Rare Diseases, Dental/Oral and Craniofacial Disease, 5.1 Pharmaceuticals, Carcinoma, Squamous Cell, Cell Line, Tumor, Cell Survival, Cetuximab, Drug Resistance, Neoplasm, Head and Neck Neoplasms, Humans, Nuclear Proteins, Proteins, Receptor Protein-Tyrosine Kinases, Receptor, ErbB-2, Signal Transduction, Squamous Cell Carcinoma of Head and Neck, Transcription Factors, Receptor, erbB-2, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Cetuximab, the FDA-approved anti-EGFR antibody for head and neck squamous cell carcinoma (HNSCC), has displayed limited efficacy due to the emergence of intrinsic and acquired resistance. We and others have demonstrated that cetuximab resistance in HNSCC is driven by alternative receptor tyrosine kinases (RTK), including HER3, MET, and AXL. In an effort to overcome cetuximab resistance and circumvent toxicities associated with the administration of multiple RTK inhibitors, we sought to identify a common molecular target that regulates expression of multiple RTK. Bromodomain-containing protein-4 (BRD4) has been shown to regulate the transcription of various RTK in the context of resistance to PI3K and HER2 inhibition in breast cancer models. We hypothesized that, in HNSCC, targeting BRD4 could overcome cetuximab resistance by depleting alternative RTK expression. We generated independent models of cetuximab resistance in HNSCC cell lines and interrogated their RTK and BRD4 expression profiles. Cetuximab-resistant clones displayed increased expression and activation of several RTK, such as MET and AXL, as well as an increased percentage of BRD4-expressing cells. Both genetic and pharmacologic inhibition of BRD4 abrogated cell viability in models of acquired and intrinsic cetuximab resistance and was associated with a robust decrease in alternative RTK expression by cetuximab. Combined treatment with cetuximab and bromodomain inhibitor JQ1 significantly delayed acquired resistance and RTK upregulation in patient-derived xenograft models of HNSCC. These findings indicate that the combination of cetuximab and bromodomain inhibition may be a promising therapeutic strategy for patients with HNSCC.Significance: Inhibition of bromodomain protein BRD4 represents a potential therapeutic strategy to circumvent the toxicities and financial burden of targeting the multiple receptor tyrosine kinases that drive cetuximab resistance in HNSCC and NSCLC.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/15/4331/F1.large.jpg Cancer Res; 78(15); 4331-43. ©2018 AACR.

Published
2018

4. Cross-talk Signaling between HER3 and HPV16 E6 and E7 Mediates Resistance to PI3K Inhibitors in Head and Neck Cancer

Author

Brand, Toni M, Hartmann, Stefan, Bhola, Neil E, Li, Hua, Zeng, Yan, O'Keefe, Rachel A, Ranall, Max V, Bandyopadhyay, Sourav, Soucheray, Margaret, Krogan, Nevan J, Kemp, Carolyn, Duvvuri, Umamaheswar, LaVallee, Theresa, Johnson, Daniel E, Ozbun, Michelle A, Bauman, Julie E, and Grandis, Jennifer R

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cervical Cancer, Dental/Oral and Craniofacial Disease, Sexually Transmitted Infections, Cancer, Infectious Diseases, Biotechnology, Women's Health, Rare Diseases, 5.1 Pharmaceuticals, Animals, Antineoplastic Agents, Cell Line, Tumor, Disease Models, Animal, Gene Knockdown Techniques, Head and Neck Neoplasms, Humans, Oncogene Proteins, Viral, Papillomavirus E7 Proteins, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Protein Binding, Receptor, ErbB-3, Repressor Proteins, Signal Transduction, Xenograft Model Antitumor Assays, Receptor, erbB-3, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Human papillomavirus (HPV) type 16 is implicated in approximately 75% of head and neck squamous cell carcinomas (HNSCC) that arise in the oropharynx, where viral expression of the E6 and E7 oncoproteins promote cellular transformation, tumor growth, and maintenance. An important oncogenic signaling pathway activated by E6 and E7 is the PI3K pathway, a key driver of carcinogenesis. The PI3K pathway is also activated by mutation or amplification of PIK3CA in over half of HPV(+) HNSCC. In this study, we investigated the efficacy of PI3K-targeted therapies in HPV(+) HNSCC preclinical models and report that HPV(+) cell line- and patient-derived xenografts are resistant to PI3K inhibitors due to feedback signaling emanating from E6 and E7. Receptor tyrosine kinase profiling indicated that PI3K inhibition led to elevated expression of the HER3 receptor, which in turn increased the abundance of E6 and E7 to promote PI3K inhibitor resistance. Targeting HER3 with siRNA or the mAb CDX-3379 reduced E6 and E7 abundance and enhanced the efficacy of PI3K-targeted therapies. Together, these findings suggest that cross-talk between HER3 and HPV oncoproteins promotes resistance to PI3K inhibitors and that cotargeting HER3 and PI3K may be an effective therapeutic strategy in HPV(+) tumors.Significance: These findings suggest a new therapeutic combination that may improve outcomes in HPV(+) head and neck cancer patients. Cancer Res; 78(9); 2383-95. ©2018 AACR.

Published
2018

5. Human Papillomavirus Regulates HER3 Expression in Head and Neck Cancer: Implications for Targeted HER3 Therapy in HPV+ Patients

Author

Brand, Toni M, Hartmann, Stefan, Bhola, Neil E, Peyser, Noah D, Li, Hua, Zeng, Yan, Wechsler, Erin Isaacson, Ranall, Max V, Bandyopadhyay, Sourav, Duvvuri, Umamaheswar, LaVallee, Theresa M, Jordan, Richard CK, Johnson, Daniel E, and Grandis, Jennifer R

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Clinical Research, Sexually Transmitted Infections, Cervical Cancer, Women's Health, Cancer, Rare Diseases, Infectious Diseases, Dental/Oral and Craniofacial Disease, Animals, Carcinoma, Squamous Cell, Cell Line, Tumor, Elafin, Gene Expression Regulation, Neoplastic, Gene Expression Regulation, Viral, Head and Neck Neoplasms, Human papillomavirus 16, Humans, Mice, Molecular Targeted Therapy, Oncogene Proteins, Viral, Papillomavirus E7 Proteins, Papillomavirus Infections, RNA, Small Interfering, Receptor, ErbB-3, Repressor Proteins, Squamous Cell Carcinoma of Head and Neck, Xenograft Model Antitumor Assays, Receptor, erbB-3, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis
Abstract

Purpose: Human papillomavirus (HPV) 16 plays an etiologic role in a growing subset of head and neck squamous cell carcinomas (HNSCC), where viral expression of the E6 and E7 oncoproteins is necessary for tumor growth and maintenance. Although patients with HPV+ tumors have a more favorable prognosis, there are currently no HPV-selective therapies. Recent studies identified differential receptor tyrosine kinase (RTK) profiles in HPV+ versus HPV- tumors. One such RTK, HER3, is overexpressed and interacts with phosphoinositide-3-kinase (PI3K) in HPV+ tumors. Therefore, we investigated the role of HPV oncoproteins in regulating HER3-mediated signaling and determined whether HER3 could be a molecular target in HPV+ HNSCC.Experimental Design: HER3 was investigated as a molecular target in HPV+ HNSCC using established cell lines, patient-derived xenografts (PDX), and human tumor specimens. A mechanistic link between HPV and HER3 was examined by augmenting E6 and E7 expression levels in HNSCC cell lines. The dependency of HPV+ and HPV- HNSCC models on HER3 was evaluated with anti-HER3 siRNAs and the clinical stage anti-HER3 monoclonal antibody KTN3379.Results: HER3 was overexpressed in HPV+ HNSCC, where it was associated with worse overall survival in patients with pharyngeal cancer. Further investigation indicated that E6 and E7 regulated HER3 protein expression and downstream PI3K pathway signaling. Targeting HER3 with siRNAs or KTN3379 significantly inhibited the growth of HPV+ cell lines and PDXs.Conclusions: This study uncovers a direct relationship between HPV infection and HER3 in HNSCC and provides a rationale for the clinical evaluation of targeted HER3 therapy for the treatment of HPV+ patients. Clin Cancer Res; 23(12); 3072-83. ©2016 AACR.

Published
2017

7. Supplementary Table S6 from Multiple Routes to Oncogenesis Are Promoted by the Human Papillomavirus–Host Protein Network

Author

Eckhardt, Manon, primary, Zhang, Wei, primary, Gross, Andrew M., primary, Von Dollen, John, primary, Johnson, Jeffrey R., primary, Franks-Skiba, Kathleen E., primary, Swaney, Danielle L., primary, Johnson, Tasha L., primary, Jang, Gwendolyn M., primary, Shah, Priya S., primary, Brand, Toni M., primary, Archambault, Jacques, primary, Kreisberg, Jason F., primary, Grandis, Jennifer R., primary, Ideker, Trey, primary, and Krogan, Nevan J., primary

Published
2023
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8. Data from Multiple Routes to Oncogenesis Are Promoted by the Human Papillomavirus–Host Protein Network

Author

Eckhardt, Manon, primary, Zhang, Wei, primary, Gross, Andrew M., primary, Von Dollen, John, primary, Johnson, Jeffrey R., primary, Franks-Skiba, Kathleen E., primary, Swaney, Danielle L., primary, Johnson, Tasha L., primary, Jang, Gwendolyn M., primary, Shah, Priya S., primary, Brand, Toni M., primary, Archambault, Jacques, primary, Kreisberg, Jason F., primary, Grandis, Jennifer R., primary, Ideker, Trey, primary, and Krogan, Nevan J., primary

Published
2023
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12. Supplementary Document S1 from Multiple Routes to Oncogenesis Are Promoted by the Human Papillomavirus–Host Protein Network

Author

Eckhardt, Manon, primary, Zhang, Wei, primary, Gross, Andrew M., primary, Von Dollen, John, primary, Johnson, Jeffrey R., primary, Franks-Skiba, Kathleen E., primary, Swaney, Danielle L., primary, Johnson, Tasha L., primary, Jang, Gwendolyn M., primary, Shah, Priya S., primary, Brand, Toni M., primary, Archambault, Jacques, primary, Kreisberg, Jason F., primary, Grandis, Jennifer R., primary, Ideker, Trey, primary, and Krogan, Nevan J., primary

Published
2023
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13. Supplemental Figure 4 from Cross-talk Signaling between HER3 and HPV16 E6 and E7 Mediates Resistance to PI3K Inhibitors in Head and Neck Cancer

Author

Brand, Toni M., primary, Hartmann, Stefan, primary, Bhola, Neil E., primary, Li, Hua, primary, Zeng, Yan, primary, O'Keefe, Rachel A., primary, Ranall, Max V., primary, Bandyopadhyay, Sourav, primary, Soucheray, Margaret, primary, Krogan, Nevan J., primary, Kemp, Carolyn, primary, Duvvuri, Umamaheswar, primary, LaVallee, Theresa, primary, Johnson, Daniel E., primary, Ozbun, Michelle A., primary, Bauman, Julie E., primary, and Grandis, Jennifer R., primary

Published
2023
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14. Supplemental Table 2 from AXL Is a Logical Molecular Target in Head and Neck Squamous Cell Carcinoma

Author

Brand, Toni M., primary, Iida, Mari, primary, Stein, Andrew P., primary, Corrigan, Kelsey L., primary, Braverman, Cara M., primary, Coan, John P., primary, Pearson, Hannah E., primary, Bahrar, Harsh, primary, Fowler, Tyler L., primary, Bednarz, Bryan P., primary, Saha, Sandeep, primary, Yang, David, primary, Gill, Parkash S., primary, Lingen, Mark W., primary, Saloura, Vassiliki, primary, Villaflor, Victoria M., primary, Salgia, Ravi, primary, Kimple, Randall J., primary, and Wheeler, Deric L., primary

Published
2023
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15. Supplemental Figure 3 from AXL Is a Logical Molecular Target in Head and Neck Squamous Cell Carcinoma

Author

Brand, Toni M., primary, Iida, Mari, primary, Stein, Andrew P., primary, Corrigan, Kelsey L., primary, Braverman, Cara M., primary, Coan, John P., primary, Pearson, Hannah E., primary, Bahrar, Harsh, primary, Fowler, Tyler L., primary, Bednarz, Bryan P., primary, Saha, Sandeep, primary, Yang, David, primary, Gill, Parkash S., primary, Lingen, Mark W., primary, Saloura, Vassiliki, primary, Villaflor, Victoria M., primary, Salgia, Ravi, primary, Kimple, Randall J., primary, and Wheeler, Deric L., primary

Published
2023
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16. Supplemental Table 1 from AXL Is a Logical Molecular Target in Head and Neck Squamous Cell Carcinoma

Author

Brand, Toni M., primary, Iida, Mari, primary, Stein, Andrew P., primary, Corrigan, Kelsey L., primary, Braverman, Cara M., primary, Coan, John P., primary, Pearson, Hannah E., primary, Bahrar, Harsh, primary, Fowler, Tyler L., primary, Bednarz, Bryan P., primary, Saha, Sandeep, primary, Yang, David, primary, Gill, Parkash S., primary, Lingen, Mark W., primary, Saloura, Vassiliki, primary, Villaflor, Victoria M., primary, Salgia, Ravi, primary, Kimple, Randall J., primary, and Wheeler, Deric L., primary

Published
2023
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18. Supplemental Figure 1 from AXL Is a Logical Molecular Target in Head and Neck Squamous Cell Carcinoma

Author

Brand, Toni M., primary, Iida, Mari, primary, Stein, Andrew P., primary, Corrigan, Kelsey L., primary, Braverman, Cara M., primary, Coan, John P., primary, Pearson, Hannah E., primary, Bahrar, Harsh, primary, Fowler, Tyler L., primary, Bednarz, Bryan P., primary, Saha, Sandeep, primary, Yang, David, primary, Gill, Parkash S., primary, Lingen, Mark W., primary, Saloura, Vassiliki, primary, Villaflor, Victoria M., primary, Salgia, Ravi, primary, Kimple, Randall J., primary, and Wheeler, Deric L., primary

Published
2023
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19. Supplemental Figure 3 from Cross-talk Signaling between HER3 and HPV16 E6 and E7 Mediates Resistance to PI3K Inhibitors in Head and Neck Cancer

Author

Brand, Toni M., primary, Hartmann, Stefan, primary, Bhola, Neil E., primary, Li, Hua, primary, Zeng, Yan, primary, O'Keefe, Rachel A., primary, Ranall, Max V., primary, Bandyopadhyay, Sourav, primary, Soucheray, Margaret, primary, Krogan, Nevan J., primary, Kemp, Carolyn, primary, Duvvuri, Umamaheswar, primary, LaVallee, Theresa, primary, Johnson, Daniel E., primary, Ozbun, Michelle A., primary, Bauman, Julie E., primary, and Grandis, Jennifer R., primary

Published
2023
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20. Supplemental Figure 1 from Human Papillomavirus Regulates HER3 Expression in Head and Neck Cancer: Implications for Targeted HER3 Therapy in HPV+ Patients

Author

Brand, Toni M., primary, Hartmann, Stefan, primary, Bhola, Neil E., primary, Peyser, Noah D., primary, Li, Hua, primary, Zeng, Yan, primary, Isaacson Wechsler, Erin, primary, Ranall, Max V., primary, Bandyopadhyay, Sourav, primary, Duvvuri, Umamaheswar, primary, LaVallee, Theresa M., primary, Jordan, Richard C.K., primary, Johnson, Daniel E., primary, and Grandis, Jennifer R., primary

Published
2023
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21. Supplemental Materials and Methods from AXL Is a Logical Molecular Target in Head and Neck Squamous Cell Carcinoma

Author

Brand, Toni M., primary, Iida, Mari, primary, Stein, Andrew P., primary, Corrigan, Kelsey L., primary, Braverman, Cara M., primary, Coan, John P., primary, Pearson, Hannah E., primary, Bahrar, Harsh, primary, Fowler, Tyler L., primary, Bednarz, Bryan P., primary, Saha, Sandeep, primary, Yang, David, primary, Gill, Parkash S., primary, Lingen, Mark W., primary, Saloura, Vassiliki, primary, Villaflor, Victoria M., primary, Salgia, Ravi, primary, Kimple, Randall J., primary, and Wheeler, Deric L., primary

Published
2023
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22. Supplemental Table 4 from AXL Is a Logical Molecular Target in Head and Neck Squamous Cell Carcinoma

Author

Brand, Toni M., primary, Iida, Mari, primary, Stein, Andrew P., primary, Corrigan, Kelsey L., primary, Braverman, Cara M., primary, Coan, John P., primary, Pearson, Hannah E., primary, Bahrar, Harsh, primary, Fowler, Tyler L., primary, Bednarz, Bryan P., primary, Saha, Sandeep, primary, Yang, David, primary, Gill, Parkash S., primary, Lingen, Mark W., primary, Saloura, Vassiliki, primary, Villaflor, Victoria M., primary, Salgia, Ravi, primary, Kimple, Randall J., primary, and Wheeler, Deric L., primary

Published
2023
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23. Supplemental Table I from Cross-talk Signaling between HER3 and HPV16 E6 and E7 Mediates Resistance to PI3K Inhibitors in Head and Neck Cancer

Author

Brand, Toni M., primary, Hartmann, Stefan, primary, Bhola, Neil E., primary, Li, Hua, primary, Zeng, Yan, primary, O'Keefe, Rachel A., primary, Ranall, Max V., primary, Bandyopadhyay, Sourav, primary, Soucheray, Margaret, primary, Krogan, Nevan J., primary, Kemp, Carolyn, primary, Duvvuri, Umamaheswar, primary, LaVallee, Theresa, primary, Johnson, Daniel E., primary, Ozbun, Michelle A., primary, Bauman, Julie E., primary, and Grandis, Jennifer R., primary

Published
2023
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27. Supplemental Figure Legends from AXL Is a Logical Molecular Target in Head and Neck Squamous Cell Carcinoma

Author

Brand, Toni M., primary, Iida, Mari, primary, Stein, Andrew P., primary, Corrigan, Kelsey L., primary, Braverman, Cara M., primary, Coan, John P., primary, Pearson, Hannah E., primary, Bahrar, Harsh, primary, Fowler, Tyler L., primary, Bednarz, Bryan P., primary, Saha, Sandeep, primary, Yang, David, primary, Gill, Parkash S., primary, Lingen, Mark W., primary, Saloura, Vassiliki, primary, Villaflor, Victoria M., primary, Salgia, Ravi, primary, Kimple, Randall J., primary, and Wheeler, Deric L., primary

Published
2023
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28. Supplemental Figure 2 from Cross-talk Signaling between HER3 and HPV16 E6 and E7 Mediates Resistance to PI3K Inhibitors in Head and Neck Cancer

Author

Brand, Toni M., primary, Hartmann, Stefan, primary, Bhola, Neil E., primary, Li, Hua, primary, Zeng, Yan, primary, O'Keefe, Rachel A., primary, Ranall, Max V., primary, Bandyopadhyay, Sourav, primary, Soucheray, Margaret, primary, Krogan, Nevan J., primary, Kemp, Carolyn, primary, Duvvuri, Umamaheswar, primary, LaVallee, Theresa, primary, Johnson, Daniel E., primary, Ozbun, Michelle A., primary, Bauman, Julie E., primary, and Grandis, Jennifer R., primary

Published
2023
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30. Supplemental Table 3 from AXL Is a Logical Molecular Target in Head and Neck Squamous Cell Carcinoma

Author

Brand, Toni M., primary, Iida, Mari, primary, Stein, Andrew P., primary, Corrigan, Kelsey L., primary, Braverman, Cara M., primary, Coan, John P., primary, Pearson, Hannah E., primary, Bahrar, Harsh, primary, Fowler, Tyler L., primary, Bednarz, Bryan P., primary, Saha, Sandeep, primary, Yang, David, primary, Gill, Parkash S., primary, Lingen, Mark W., primary, Saloura, Vassiliki, primary, Villaflor, Victoria M., primary, Salgia, Ravi, primary, Kimple, Randall J., primary, and Wheeler, Deric L., primary

Published
2023
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31. Supplemental Figure 2 from AXL Is a Logical Molecular Target in Head and Neck Squamous Cell Carcinoma

Author

Brand, Toni M., primary, Iida, Mari, primary, Stein, Andrew P., primary, Corrigan, Kelsey L., primary, Braverman, Cara M., primary, Coan, John P., primary, Pearson, Hannah E., primary, Bahrar, Harsh, primary, Fowler, Tyler L., primary, Bednarz, Bryan P., primary, Saha, Sandeep, primary, Yang, David, primary, Gill, Parkash S., primary, Lingen, Mark W., primary, Saloura, Vassiliki, primary, Villaflor, Victoria M., primary, Salgia, Ravi, primary, Kimple, Randall J., primary, and Wheeler, Deric L., primary

Published
2023
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36. Data Supplement from AXL Mediates Resistance to Cetuximab Therapy

Author

Brand, Toni M., primary, Iida, Mari, primary, Stein, Andrew P., primary, Corrigan, Kelsey L., primary, Braverman, Cara M., primary, Luthar, Neha, primary, Toulany, Mahmoud, primary, Gill, Parkash S., primary, Salgia, Ravi, primary, Kimple, Randall J., primary, and Wheeler, Deric L., primary

Published
2023
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37. Data from AXL Mediates Resistance to Cetuximab Therapy

Author

Brand, Toni M., primary, Iida, Mari, primary, Stein, Andrew P., primary, Corrigan, Kelsey L., primary, Braverman, Cara M., primary, Luthar, Neha, primary, Toulany, Mahmoud, primary, Gill, Parkash S., primary, Salgia, Ravi, primary, Kimple, Randall J., primary, and Wheeler, Deric L., primary

Published
2023
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38. Editor's Note: Cross-talk Signaling between HER3 and HPV16 E6 and E7 Mediates Resistance to PI3K Inhibitors in Head and Neck Cancer

Author

Brand, Toni M., primary, Hartmann, Stefan, additional, Bhola, Neil E., additional, Li, Hua, additional, Zeng, Yan, additional, O'Keefe, Rachel A., additional, Ranall, Max V., additional, Bandyopadhyay, Sourav, additional, Soucheray, Margaret, additional, Krogan, Nevan J., additional, Kemp, Carolyn, additional, Duvvuri, Umamaheswar, additional, LaVallee, Theresa, additional, Johnson, Daniel E., additional, Ozbun, Michelle A., additional, Bauman, Julie E., additional, and Grandis, Jennifer R., additional

Published
2022
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39. Correction: Cross-talk Signaling between HER3 and HPV16 E6 and E7 Mediates Resistance to PI3K Inhibitors in Head and Neck Cancer

Author

Brand, Toni M., primary, Hartmann, Stefan, additional, Bhola, Neil E., additional, Li, Hua, additional, Zeng, Yan, additional, O'Keefe, Rachel A., additional, Ranall, Max V., additional, Bandyopadhyay, Sourav, additional, Soucheray, Margaret, additional, Krogan, Nevan J., additional, Kemp, Carolyn, additional, Duvvuri, Umamaheswar, additional, LaVallee, Theresa, additional, Johnson, Daniel E., additional, Ozbun, Michelle A., additional, Bauman, Julie E., additional, and Grandis, Jennifer R., additional

Published
2022
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42. Retraction

Author

Brand, Toni M., primary, Iida, Mari, additional, Corrigan, Kelsey L., additional, Braverman, Cara M., additional, Coan, John P., additional, Flanigan, Bailey G., additional, Stein, Andrew P., additional, Salgia, Ravi, additional, Rolff, Jana, additional, Kimple, Randall J., additional, and Wheeler, Deric L., additional

Published
2021
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43. Correction: Human Papillomavirus Regulates HER3 Expression in Head and Neck Cancer: Implications for Targeted HER3 Therapy in HPV+ Patients

Author

Brand, Toni M., primary, Hartmann, Stefan, additional, Bhola, Neil E., additional, Peyser, Noah D., additional, Li, Hua, additional, Zeng, Yan, additional, Wechsler, Erin Isaacson, additional, Ranall, Max V., additional, Bandyopadhyay, Sourav, additional, Duvvuri, Umamaheswar, additional, LaVallee, Theresa M., additional, Jordan, Richard C.K., additional, Johnson, Daniel E., additional, and Grandis, Jennifer R., additional

Published
2021
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47. Correction: AXL Is a Logical Molecular Target in Head and Neck Squamous Cell Carcinoma

Author

Brand, Toni M., primary, Iida, Mari, additional, Stein, Andrew P., additional, Corrigan, Kelsey L., additional, Braverman, Cara M., additional, Coan, John P., additional, Pearson, Hannah E., additional, Bahrar, Harsh, additional, Fowler, Tyler L., additional, Bednarz, Bryan P., additional, Saha, Sandeep, additional, Yang, David, additional, Gill, Parkash S., additional, Lingen, Mark W., additional, Saloura, Vassiliki, additional, Villaflor, Victoria M., additional, Salgia, Ravi, additional, Kimple, Randall J., additional, and Wheeler, Deric L., additional

Published
2018
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48. KRAS mutant colorectal tumors

Author

Brand, Toni M. and Wheeler, Deric L.

Subjects
Male, EGFR, Immunoblotting, Dasatinib, Cetuximab, Mice, Nude, Antineoplastic Agents, Apoptosis, Antibodies, Monoclonal, Humanized, resistance, Proto-Oncogene Proteins p21(ras), Mice, Cell Line, Tumor, Proto-Oncogene Proteins, Antineoplastic Combined Chemotherapy Protocols, KRAS, Animals, Humans, neoplasms, GTPase, Protein Kinase Inhibitors, Cell Proliferation, metastatic colorectal cancer, Antibodies, Monoclonal, Drug Synergism, HCT116 Cells, Xenograft Model Antitumor Assays, digestive system diseases, ErbB Receptors, Thiazoles, Pyrimidines, src-Family Kinases, Drug Resistance, Neoplasm, Mutation, Commentary, ras Proteins, RNA Interference, Caco-2 Cells, Colorectal Neoplasms
Abstract

KRAS mutation is a predictive biomarker for resistance to cetuximab (Erbitux) in metastatic colorectal cancer (mCRC). This study sought to determine if KRAS mutant CRC lines could be sensitized to cetuximab using dasatinib (BMS-354825, Sprycel), a potent, orally bioavailable inhibitor of several tyrosine kinases, including the Src family kinases (SFKs). We analyzed 16 CRC lines for: (1) KRAS mutation status, (2) dependence on mutant KRAS signaling and (3) expression level of epidermal growth factor receptor (EGFR) and SFKs. From these analyses, we selected three KRAS mutant (LS180, LoVo and HCT116) cell lines and two KRAS wild-type cell lines (SW48 and CaCo2). In vitro, using poly-D-lysine/laminin plates, KRAS mutant cell lines were resistant to cetuximab, whereas KRAS wild-type lines showed sensitivity to cetuximab. Treatment with cetuximab and dasatinib showed a greater antiproliferative effect on KRAS mutant lines when compared with either agent alone in vitro and in vivo. To investigate potential mechanisms for this antiproliferative response in the combinatorial therapy, we performed Human Phospho-Kinase Antibody Array analysis, measuring the relative phosphorylation levels of 39 intracellular proteins in untreated, cetuximab, dasatinib or the combinatorial treatment in the KRAS mutant lines LS180, LoVo and HCT116 cells. The results of this experiment showed a decrease in a broad spectrum of kinases centered on the β-catenin pathway, the mitogen-activated protein kinase (MAPK) pathway, AKT/mammalian target of rapamycin (mTOR) pathway and the family of signal transducers and activators of transcription (STATs) when compared with the untreated control or monotherapy treatments. Next, we analyzed tumor growth with cetuximab, dasatinib or their combination in vivo. KRAS mutant xenografts showed resistance to cetuximab therapy, whereas KRAS wild type demonstrated an antitumor response when treated with cetuximab. KRAS mutant tumors exhibited minimal response to dasatinib monotherapy. However, as in vitro, KRAS mutant lines exhibited a response to the combination of cetuximab and dasatinib. Combinatorial treatment of KRAS mutant xenografts resulted in decreased cell proliferation, as measured by Ki67, and higher rates of apoptosis, as measured by TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling). The data presented in this study indicate that dasatinib can sensitize KRAS mutant CRC tumors to cetuximab and may do so by altering the activity of several key signaling pathways. Furthermore, these results suggest that signaling via EGFR and SFKs may be necessary for cell proliferation and survival of KRAS mutant CRC tumors. These data strengthen the rationale for clinical trials combining cetuximab and dasatinib in the KRAS mutant CRC genetic setting.

Published
2012

49. Abstract A140: MERTK mediates intrinsic and adaptive resistance to AXL-targeting agents

Author

McDaniel, Nellie K., primary, Cummings, Christopher T., additional, Brand, Toni M., additional, Iida, Mari, additional, Hulse, Justus, additional, Pearson, Hannah E., additional, Orbuch, Rachel A., additional, Ondracek, Olivia J., additional, Davies, Kurtis D., additional, Gill, Parkash, additional, Wang, Xiaodong, additional, Frye, Stephen V., additional, Earp, H. Shelton, additional, Kimple, Randall J., additional, Harari, Paul M., additional, DeRyckere, Deborah, additional, Graham, Douglas K., additional, and Wheeler, Deric L., additional

Published
2018
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50. Abstract PR04: HER3 crosstalk with HPV16-E6E7 is a feedback resistance mechanism to PI3K-targeted therapies in head and neck cancer

Author

Brand, Toni M., primary, Hartmann, Stefan, additional, Bhola, Neil E., additional, Li, Hua, additional, Zeng, Yan, additional, O'Keefe, Rachel, additional, Ranall, Max V., additional, Bandyopadhyay, Sourav, additional, Soucheray, Margaret, additional, Swaney, Danielle L., additional, Krogan, Nevan, additional, Kemp, Carolyn, additional, Duvvuri, Umamaheswar, additional, Johnson, Daniel E., additional, Ozbun, Michelle A., additional, Bauman, Julie E., additional, and Grandis, Jennifer R., additional

Published
2017
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