Abstract 4290: c-Myc and Ras differentially regulate mitochondrial apoptotic priming and chemosensitivity.

Successful treatment of most human cancers is dependent on tumor cell sensitivity to chemotherapy yet the basis for chemosensitivity is poorly understood. We have previously shown that a cancer9s proximity to the apoptotic threshold, a property we call "apoptotic priming," governs its chemosensitivity in patients with multiple myeloma, ALL, AML and ovarian cancer. The genetic and molecular events that underlie the differential priming in tumors, however, are currently unknown. Utilizing in vitro ovarian, kidney and lung tumorigenesis models we find that oncogenes are powerful modulators of apoptotic priming and are consequently responsible for differential chemosensitivity. For example, forced expression of the c-Myc oncogene increases priming and chemosensitivity of immortalized normal epithelium. In contrast, Ras activation in isogenic cells dramatically decreases both priming and chemosensitivity. Our in vitro findings are validated by clinical observations. Apoptotic priming, an important determinant of patient outcomes, is modulated in contrasting manners by oncogenes. Citation Format: Kristopher A. Sarosiek, Triona Ni Chonghaile, Alison Karst, Luv Patel, Ronny Drapkin, Anthony Letai. c-Myc and Ras differentially regulate mitochondrial apoptotic priming and chemosensitivity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4290. doi:10.1158/1538-7445.AM2013-4290