Targeting KRAS-mutant NSCLC through inhibition of MTOR and Hsp90

A significant fraction of NSCLC have mutant KRAS which predicts poor response to cytotoxic therapy and portends a poor prognosis. Despite the discovery of the first mutation in the KRAS oncogene in NSCLC over two decades ago, there are no current therapies targeting this critical oncogene. In this proposal we explore a novel and exciting therapeutic strategy to target KRAS-mutant NSCLC through the combination of Hsp90 and mTOR inhibition. We have preclinical evidence suggesting that the combination of ganetespib and an mTOR inhibitor may be an effective therapeutic strategy for patients with KRAS- mutant NSCLC. In Aim 1, we will define resistance mechanisms to single-agent ganetespib in KRAS- mutant NSCLC. The identification of resistance mechanisms to single-agent ganetespib will reveal novel pathways that we can then target in combination with an Hsp90 inhibitor. In Aim 2, we will test the hypothesis that activation of the mTOR pathway through alterations in STK11 or PI3KCA mutations will predict response to the combination. Finally, in Aim 3 we will translate our studies to the clinic in a phase I/II trial of the combination of ganetespib and an mTOR inhibitor in patients with advanced KRAS-mutant lung adenocarcinoma. Importantly, we will have correlative studies looking at response in subpopulations of KRAS-mutant tumors that are hyperactive for the mTOR pathway (STK11, PIK3CA mutations). This translational approach will allow us to identify biomarkers that we can use to effectively target this combination to the patients with greatest chance to benefit from this therapy.