Abstract 932: Selective requirement of BH3-only proteins for apoptosis induced by targeted therapies in colon cancer cells and xenografts

Abstract

Abstract Constitutive activation of pro-survival kinases has become a promising target of recently developed small molecules, while their biomarkers and resistance mechanisms remain largely unknown. In this study, we investigated the role of several BH3-only proteins PUMA, Bim and Noxa in apoptosis and growth suppression induced by different classes of targeted agents, including selective small molecule inhibitors to c-Met, IGFR, Hsp90, VEGFR and non selective kinases inhibitors in colon cancer cells and xenografts. Using isogenic colon cancer cells with targeted deletion in PUMA, Bim or Noxa, we demonstrated universal and persistent PUMA induction by all of these agents, which is mediated by either p53-dependent or -independent mechanisms. PUMA deficiency led to impaired apoptosis and caspase activation in colon cancer cells, and significantly blocked tumor cell apoptosis and therapeutic responses to these agents in xenografts. On the contrary, modulation of upstream signaling such as phosphorylation of PI3K/AKT was transient and involves diverse transcription factors. Interestingly, only a small subset of agents induced the expression of Bim or Noxa, or required Bim or Noxa for apoptosis induction. Moreover, small molecule BH3 mimetics, or enhanced PUMA levels resulted from another drug sensitized colon cancer cells to apoptosis induced by majority of these agents. Our results establish a critical role of the mitochondrial pathway and BH3-only proteins in mediating sensitivity of colon cancer cells to a wide variety of targeted-agents, and shed light on resistance mechanisms. In light of recent data on BH3-only proteins in therapy-induced apoptosis in other tumor types, our data suggest that modulations of selected BH3-only proteins, rather than their steady-state levels, might sever as potential biomarkers for predicting therapeutic responses in both treatment-naïve and pretreated patients, and provide a rationale for combination therapy in clinical trials. These novel preclinical findings can help guide future development and clinical use of targeted agents. Key words: kinase inhibitors; PUMA; Bim; Noxa; apoptosis; resistance mechanisms, colon cancer Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 932. doi:1538-7445.AM2012-932