mTOR

KRAS mutations activate signaling from downstream effector proteins and are though to be required for tumor formation. Exactly how effector signaling is activated, however, is not fully understood. In addition, whether tumors harboring KRAS mutations depend on this oncogene for growth is unclear.

Dr. Lito and his group will dissect the phenotype of KRAS-mutant lung cancer by using a novel allosteric inhibitor that selectively targets KRAS G12C. They will first utilize biochemical assays in order to determine the mechanism of action of this inhibitor. An emphasis will be placed on evaluating how feedback pathways modulate this process, since this is likely to identify factors that may be used as biomarkers of response to treatment.

They will then determine which effector pathways drive the phenotype of KRAS G12C mutant lung cancer, and whether these exhibit adaptation (or reactivation) over time. If so, they will next explore combination-based interventions in order to establish the most effective antiproliferative strategy.

Finally, they will utilize novel patient-derived xenograft and cell line models, established from patients with lung cancer treated at MSKCC, in order to determine if KRAS G12C mutant lung cancers depend on this oncoprotein for growth. These models will also be used to test the most effective combination strategies determined above, as well as to test the potential benefit of intermittent administration schemes designed to best target tumor adaptation to this novel class of inhibitors.

The grand objective of this project is to establish a mutant KRAS-directed therapy for patients with lung cancer. 

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.