Abstract 3122: Pharmacogenomic profiling to identify novel therapeutic strategies in colorectal cancer

Abstract

Abstract Colorectal cancer (CRC) is amongst the most frequent cancers worldwide and the fourth most common cause of cancer mortality. Surgery is the standard treatment of care, while chemotherapy and/or radiotherapy are offered to subgroups of patients according to disease stage. Current guidelines do not have sufficient accuracy to identify chemotherapy responders, resulting in under- or overtreatment of many patients.To discover novel therapeutic strategies for CRC we performed a high-throughput drug screen containing 461 approved and preclinical drugs on a representative panel of 42 CRC cell lines. Integrative pharmacogenomic profiles were explored by matching data from gene expression, exome sequencing, copy number and reverse-phase protein arrays. These analyses identified defined molecular subgroups sensitive to targeted drugs like Inhibitors of EGFR, IGF-1R and downstream signaling mediators like B-Raf, MEK, PI3K/AKT, as well as inhibitors of aurora mitotic kinases, heat shock protein 90 and p53. Additionally, a correlation between microsatellite instability and sensitivity against topoisomerase-I inhibitors was found. Comparison of the most sensitive and the most resistant cell models against HSP90 inhibitors indicated that drug sensitivity does not depend on target expression but is likely attributed to the cell line-specific expression of client proteins. Real-time cell analyses measured with the xCELLigence system demonstrated a strong impact on cell proliferation but not on the migration of HSP90-sensitive cells treated with HSP90 inhibitors as compared to resistant cells. These integrative analyses have unraveled pharmacogenomic relationships that if validated in in vivo model systems, might be used to stratify patients for therapeutic intervention in biomarker guided clinical trials. Citation Format: Jarle Bruun, Peter W. Eide, Kushtrim Kryeziu, Anita Sveen, Astrid Murumägi, Matthias Kolberg, Mariliina Arjama, Olli Kallioniemi, Ragnhild A. Lothe. Pharmacogenomic profiling to identify novel therapeutic strategies in colorectal cancer [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 3122. doi:10.1158/1538-7445.AM2017-3122