Molecular determinants in autophagic repression of intrinsic apoptosis

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 DESCRIPTION (provided by applicant): We have identified a novel cross-regulation pathway between autophagy and apoptosis that is mediated by a hitherto unknown complex between Atg7 and caspase-9. Our findings suggest that depending on the cellular context, Atg7 and caspase-9 reciprocally regulate each other's activity: whereas Atg7 represses the apoptotic activity of caspase-9, the latter enhances the Atg7 conjugation activity required for formation of membranous LC3-II. The current studies will center on KRAS mutant lung adenocarcinoma, which represents 40,000 newly diagnosed patients per year, for whom no effective therapies exist. The selection of this tumor model for these studies is based on its refractoriness to conventional cytotoxic therapies and its dependence on autophagy for survival, proliferation, and response to therapy. Mutant KRAS has been considered "undruggable." Yet, recent studies reported significant, but transient, single-agent activity by ganetespib, a second generation heat-shock protein 90 inhibitor, in a subset of KRAS mutant patients. Our preliminary results suggest that ganetespib- sensitive KRAS mutant Non-Small Cell Lung Cancer (NSCLC) cells respond to ganetespib mainly with growth arrest and apoptosis, whereas ganetespib-resistant cells respond with cytoprotective autophagy. We propose to investigate the newly discovered cross-regulatory pathway between Atg7 and caspase-9, and in particular, the therapeutic significance of the Atg7/caspase-9 complex itself in the autophagic response of ganetespib- resistant KRAS mutant NSCLC cells. We also propose to investigate the molecular determinants of the Atg7 repression of caspase-9 apoptotic activity. Our studies are designed to test the hypothesis that disruption of the Atg7/caspase-9 complex serves to attenuate early events in the autophagosome formation process with concomitant de-repression of caspase-9 apoptotic activity. If our hypothesis is proven correct, disruption of Atg7/caspase-9 complex in combination with ganetespib may lead to a novel approach for targeting KRAS mutant NSCLC.