1. Abstract 4104: Intrinsic and acquired resistance to cetuximab in colorectal cancer patients
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Jason C. Ting, Thejaswini Gopalappa, John N. Calley, Hui-Rong Qian, Ruslan D. Novosiadly, Christoph Reinhard, Melinda D. Willard, Philip J. Ebert, Jeeyun Lee, Swee Seong Wong, Jiangang Liu, Isabella H. Wulur, Seung Tae Kim, Amit Aggarwal, Hee Cheol Kim, and Steven M. Bray
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Oncology ,MAPK/ERK pathway ,Neuroblastoma RAS viral oncogene homolog ,Cancer Research ,medicine.medical_specialty ,biology ,Cetuximab ,business.industry ,Colorectal cancer ,Cancer ,PDGFRA ,medicine.disease ,medicine.disease_cause ,Receptor tyrosine kinase ,Internal medicine ,biology.protein ,medicine ,KRAS ,business ,medicine.drug - Abstract
Anti-EGFR antibodies, such as cetuximab, are effective therapies for many late-stage colorectal cancer (CRC) patients; unfortunately, many tumors are initially unresponsive while others show initial efficacy but eventually develop acquired resistance. Genomic studies of patient tumors, cell lines, and xenograft models have identified putative anti-EGFR resistance markers, including mutations in KRAS, NRAS, BRAF, PIK3CA, and the EGFR extracellular domain, as well as amplifications in ERBB2 and MET. In order to further confirm and identify new resistance mechanisms to anti-EGFR treatment in CRC, we performed retrospective genomic profiling of 25 CRC patients treated at Samsung Medical Center from 2006-2015. Patients received cetuximab containing chemo regimens with varying duration of responses, including acquired resistance cases. Our analysis identifies mutations in receptor tyrosine kinases, such as EGFR, NTRK1, and PDGFRA, as well as RAS/MAPK pathway genes that affect cetuximab response. We also uncover genomic alterations in ERBB2 and c-KIT as potential novel mechanisms regulating sensitivity to anti-EGFR antibodies. Additional genomic analyses of acquired resistance tumors and in vitro studies of a patient-derived cell line provide added insights into clonal selection and signaling pathways that bypass the EGFR blockade. Overall, our study elucidates important new facets in the landscape of anti-EGFR resistance mechanisms. Note: This abstract was not presented at the meeting. Citation Format: Steven M. Bray, Jeeyun Lee, Seung Tae Kim, Philip J. Ebert, John N. Calley, Isabella H. Wulur, Thejaswini Gopalappa, Swee Seong Wong, Hui-Rong Qian, Jason C. Ting, Jiangang Liu, Melinda D. Willard, Amit Aggarwal, Ruslan D. Novosiadly, Hee-Cheol Kim, Christoph Reinhard. Intrinsic and acquired resistance to cetuximab in colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4104. doi:10.1158/1538-7445.AM2017-4104
- Published
- 2017
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