The major limitation of lung cancer therapies that selectively target the Epidermal Growth Factor Receptor (EGFR) signaling network is the emergence of secondary drug resistance mechanisms. Currently, 40% of the cases of acquired resistance to EGFR Tyrosine Kinase Inhibitors (TKIs) are mechanistically unexplained. However, there are still no effective therapies for Non Small Cell Lung Cancer (NSCLC) harboring the secondary EGFR mutation, T790M, which accounts for 50% of acquired resistance to EGFR TKIs in NSCLC carrying sensitive EGFR mutations. Recent reports as well as our own preliminary findings suggest that erlotinib, an EGFR TKI, induces cytoprotective autophagy in NSCLC cells that do not succumb to its antitumor activity. Thus, independent of the molecular mechanism(s) of resistance to erlotinib, cytoprotective autophagy is invoked to overcome the cellular stress brought about by this TKI. Such a shared adaptation response of NSCLC cells with distinct erlotinib resistance mechanisms may serve as a therapeutic target for tumor cells that currently do not have any other effective therapy. Furthermore, many of the current efforts to prevent or delay the development of acquired resistance to EGFR TKIs incorporate a second agent with erlotinib in the first-line setting. In the current application, we propose to determine the therapeutic potentil of targeting a newly discovered mechanism of cross-regulation between autophagy and apoptosis as an additional component for the treatment of EGFR mutant NSCLC by erlotinib. Our preliminary studies identified a hitherto unknown complex between Atg7 and caspase-9, which is downregulated during apoptosis, but intensified during autophagy. Our preliminary data suggest that depending on the cellular context, each of the complex components cross-regulates the other's activity: while Atg7 represses the apoptotic activity of caspase-9, the latte enhances the autophagic activity of Atg7. In the current application, we propose to determine the clinical potential of a targeted disruption of the Atg7/caspase-9 complex, utilizing molecular insights produced by our preliminary studies. In particular, we suggest that a specific disruption of this complex will negatively impact the NSCLC autophagic response to erlotinib, while enhancing its apoptotic response via the removal of caspase-9 repression by Atg7. We propose 3 specific aims to test our central hypothesis that 'the Atg7/caspase-9 complex determines the balance between autophagy and apoptosis in the response of EGFR mutant NSCLC to erlotinib.' In Specific Aim 1, we plan to test the cross-regulation between Atg7 and caspase-9 in EGFR mutant NSCLC response to erlotinib.
In Specific Aim 2, we plan to investigate the significance of the Atg7/caspase-9 complex as a target for sensitization of EGFR mutant NSCLC cells to erlotinib.
In Specific Aim 3, we plan to advance the testing of the hypothesis to animal models. The proposed studies are highly innovative in both preliminary findings and potential clinical implications. The newly discovered Atg7/caspase-9 complex offers an exciting cross-regulation mechanism that may be utilized to enhance the apoptotic over the autophagic activity of erlotinib, and potentially extend its therapeutic benefit to a disease stage for which o other effective therapies are available.
This project is designed to determine the therapeutic potential of a newly discovered protein complex that cross-regulates autophagy (a cell survival mechanism) and apoptosis (a cell death mechanism). The underlying hypothesis is that the disruption of this complex will have a dual effect of inhibiting autophagy and increasing apoptosis, and therefore should be considered as an additional component in anticancer regimens that give rise to cytoprotective autophagy. This project will investigate the therapeutic significance of inhibition of the complex formation for patients with Non-Small Cell Lung Cancer that acquire resistance to Epidermal Growth Factor Receptor tyrosine kinase inhibitors. Currently, patients with acquired resistance to Epidermal Growth Factor Receptor targeting have no viable treatment options. As lung cancer is almost twice as frequent in veterans than in the general population, successful elucidation of a sensitizing component for a current therapeutic modality will be highly relevant for the treatment of this group of patients.
