Abstract 4899: Establishment and characterization of SN-38 resistant metastatic colorectal cancer cells (SW620/SN100) reveals an ABCG2 (BCRP) transport mediated resistance

Abstract

Abstract Despite advances in anticancer drug research, chemotherapy options and response rates for metastatic colorectal cancer (mCRC) are poor. Irinotecan, a topoisomerase I inhibitor, is a commonly used chemotherapy against mCRC as a single agent, or in combination with other anti-cancer drugs such as fluorouracil and leucovorin. However, acquired resistance to chemotherapy, especially in metastatic patients, is a critical cause of treatment failure. Multi-drug resistance (MDR) in cancer is a major challenge to chemotherapy success. Mechanisms of MDR involve deliberate alteration in cellular expression, function, and/or responses of the cancer. One of the most notable mechanism of MDR is an increased cellular drug efflux through up-regulation of membrane ATP-binding cassette (ABC) transporters. To investigate a new and clinically relevant mechanism of MDR in mCRC cells, SN-38 (the potent and active metabolite of irinotecan) was regularly administered to SW620 cells with drug-free intervals to reflect a drug induced resistance to treatment. Through cytotoxicity and western blotting assays on the newly formed SW620/SN100 cells, we discovered ABCG2 (BCRP) to be the main mechanism of SN-38 resistance, with no alterations in the topoisomerase I, ABCB1 (P-gp) or ABCC1 (MRP1). These results confirmed our initial hypothesis, given SN-38 is a known substrate of ABCG2. This discovery of SN-38 induced efflux in mCRC is of a larger importance because this mechanism not only limits the efficacy of the chemotherapy, but also poses a threat to the efficacy of a variety of pharmacologically dissimilar drugs which are substrates of ABCG2. As treatments for mCRC continue to be investigated it is important to also continue investigating resistant mechanisms of these drugs. More discoveries of MDR mechanisms which are specific to cancer patient populations will offer superior diagnosis, proper treatment regimens and greater prognosis for patient success. Citation Format: Anna Maria Barbuti, Zhe-Sheng Chen. Establishment and characterization of SN-38 resistant metastatic colorectal cancer cells (SW620/SN100) reveals an ABCG2 (BCRP) transport mediated resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4899.