Abstract 970: Broad therapy resistance is induced by suppression of apoptotic priming by lineage programs and oncogenic activation

Field: Biochemistry, Genetics and Molecular Biology (Life Sciences)

Abstract Understanding the mechanisms of resistance to anticancer therapies may improve personalized treatment regimens and responses to therapy. The mitochondrial apoptosis pathway is activated by most targeted and cytotoxic therapies and represents a node that may be modulated for broad therapy resistance. It has been shown that some cancers, especially those of hematopoietic origin, are primed for apoptosis (as measured by BH3 Profiling) and consequently undergo apoptosis readily in response to therapies while others are unprimed and resistant. However, despite the importance of apoptotic priming in governing response to anticancer therapies, the upstream molecular determinants of apoptotic priming are unknown. Prior work has shown that oncogenes, including c-Myc, can sensitize some cells to apoptosis. We therefore hypothesized that lineage programming and activation of oncogenes may modulate apoptotic priming in normal cells undergoing neoplastic transformation. Using numerous in vitro and in vivo ovarian, breast, kidney and liver tumorigenesis models we discovered that the strongest determinant of apoptotic priming and chemosensitivity in a cancer cell is the level of priming measured in the cell of origin. To illustrate, ovarian adenocarcinomas, which originate from primed ovarian or fallopian tube epithelia, are considerably more primed than hepatocellular carcinomas originating from unprimed precursors. Notably, we also found that activation of certain oncogenes can meaningfully increase apoptotic priming and chemosensitivity while others decrease it. For example, transformation of normal epithelial cells via forced expression of the c-Myc oncogene increased priming and chemosensitivity. In contrast, activation of Ras in isogenic cells dramatically decreased both priming and chemosensitivity. We have systematically characterized the effects of 27 oncogenes on apoptotic priming and chemosensitivity including PI3K, Notch, Src, BRAF, β-catenin, Akt, and Aurora B kinase. Certain subsets of oncogenes consistently reduced apoptotic priming in cells undergoing transformation and, in combination with cell lineage programs, established broad resistance to targeted and cytotoxic therapies. Importantly, our experimental findings are complemented by clinical correlates. Overall, this work may aid efforts to deploy personalized and efficacious cancer treatments and enhance our knowledge of how cancers evade cell death, which is a hallmark of cancer. Citation Format: Kristopher A. Sarosiek, Alison Karst, Peter Winter, Antonio Sorrentino, Sourav Bandyopadhyay, Andrei Goga, Kris C. Wood, Ronny Drapkin, Anthony Letai. Broad therapy resistance is induced by suppression of apoptotic priming by lineage programs and oncogenic activation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 970. doi:10.1158/1538-7445.AM2015-970