MEK

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.