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Abstract
Abstract Emergence of resistance to targeted therapies is a critical problem in cancer therapy, and understanding both the mechanisms of resistance and strategies for overcoming resistance are crucial to effective treatment of cancer patients. The JAX Clinical Knowledgebase (JAX-CKB), which incorporates data on therapeutic efficacy in the context of molecular alterations, enables rapid analysis of known therapy resistance mechanisms and current data surrounding strategies for overcoming resistance, both in the preclinical and clinical setting. Using the JAX-CKB, we have identified over 1250 lines of evidence corresponding to therapy resistance across tumor types. Of those lines, 147 correspond to therapy resistance in lung cancer. The JAX-CKB contains 22 variants in ALK associated with ALK therapy resistance. Within ALK fusion-positive lung cancer, evidence lines corresponding to ALK inhibitor resistance are associated primarily with complex molecular profiles containing secondary ALK mutations, and mechanisms for overcoming resistance in this setting were associated with use of novel agents. Within EGFR mutation positive lung cancer, lines associated with resistance to EGFR inhibitor therapy included copy number alterations, primary resistance mutations, secondary resistance mutations, and expression level changes. Strategies for overcoming resistance in these settings include novel agents and/or various combination therapies. The JAX-CKB provides a unique global view into current data on resistance to targeted therapies in oncology, which may enable more rapid assessment of effective therapy options and expose opportunities for additional research into strategies for overcoming resistance. Citation Format: Sara E. Patterson, Cara M. Statz, Taofei Yin, Susan M. Mockus. Analysis of drug resistance mechanisms and strategies for overcoming resistance in cancer therapy using a curated clinical knowledgebase [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 2600. doi:10.1158/1538-7445.AM2017-2600
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