Abstract 2948: Novel cell line barcoding method reveals tepoxalin as a selective drug against MDR1-high tumor cells

Abstract

Abstract Drug repurposing for cancer therapy has seen notable success, such as the reintroduction of thalidomide. To discover new indications, all existing drugs known to be safe should be systematically evaluated for anti-cancer properties. However, given cost and throughput considerations, phenotypic screens are typically limited along the cell line (e.g., NCI-60 cell lines) or compound dimension (e.g., testing only several hundred cancer drugs). To identify new repurposing opportunities at scale, we tested more than 4,600 existing drugs for cytotoxicity against 578 diverse cancer cell lines using PRISM, a recently developed multiplexed cell viability assay. High gene expression of the ABCB1 transporter (MDR1/p-glycoprotein) was strongly correlated with resistance to numerous approved cancer therapeutics including taxanes, anthracyclines, vinca alkaloids, and proteasome inhibitors. Surprisingly, we identified a single drug, tepoxalin, with the opposite profile: selective activity against MDR1-high cancer cell lines. Tepoxalin, an oral cyclooxygenase inhibitor, is FDA-approved for treatment of osteoarthritis in dogs and was previously found to be safe in human trials. To evaluate for alternative mechanism of action and genomic mediators of tepoxalin resistance, we conducted pooled genome-wide CRISPR-Cas9 modifier screens in the LS1034 colorectal cancer cell line. The CRISPR knockout screen revealed ABCB1 as the top enriched gene mediating tepoxalin resistance, while the CRISPR activation screen revealed ABCB1 as the top depleted gene. Overexpression of ABCB1 in ovarian cancer cell lines also sensitized to tepoxalin killing. Small molecule combination testing demonstrated rescue of tepoxalin killing by known ABCB1 inhibitors. Future studies will include biophysical characterization of the interaction between tepoxalin and the ABCB1 protein as well as in vivo efficacy testing. Our results demonstrate that tepoxalin or related derivatives may be useful in the treatment of chemotherapy-resistant colorectal cancer, ovarian cancer, lymphoma, and other malignancies. Citation Format: Steven M. Corsello, Ryan D. Spangler, Rohith T. Nagari, Mustafa Kocak, Jordan Rossen, Patrick O'Hearn, Jennifer Roth, Alfredo Gonzalez, Nancy Dumont, John Doench, Jesse S. Boehm, Francisca Vazquez, Aviad Tsherniak, Todd R. Golub. Novel cell line barcoding method reveals tepoxalin as a selective drug against MDR1-high tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2948.