Redefining indications of EGFR inhibitors in cancers that harbor mutant RAS

Background: Anti-EGFR agents have been shown to benefit colorectal cancer patients, except for patients whose tumor includes a KRAS mutation. Data from multiple clinical trials suggest this may be incorrect. Colorectal cancer patients with KRAS G13D appear to benefit from anti-EGFR agents. Controversy surrounds this observation because it contradicts the well-established mechanisms of EGFR signaling and Ras mutations. We have investigated the problem with a novel experimental-systems approach of Ras signaling, revealing a non-intuitive dependency on EGFR that follows from differences in how KRAS mutants interact with tumor suppressor neurofibromin (NF1) to influence wild-type RAS activation thereby. Moreover, we have identified an additional 10 mutants that so not bind NF1 and confer sensitivity to EGFR inhibition. Here we propose to study the remaining mutants that makeup over 90% of the RAS mutations in CRC. Furthermore, we have devised a strategy to selectively target WT RAS in the resistant RAS alleles to sensitize CRC to EGFR inhibitors. Overarching Hypothesis: We plan to characterize these mutants with hypothesis driven independent aims: Aim 1 Functional mechanistic studies will test RAS candidates determined by their ability to bind NF1 for EGFR inhibitor sensitivity. Aim 2 Pharmacologically target WT-RAS in CRC cells that harbor mutant KRAS alleles that confer intrinsic resistance to EGFR inhibitors. Aim 3 Leverage dominant/negative effects of cytosolic NRAS mutants with EGFR inhibition. Long term goal: It is increasingly believed that combining experimental and computational methods will be required to match patients with treatments. Our work demonstrates how systems approaches enable mechanism-based inference concerning how mutations influence the response to treatment. Our current findings suggest that we can identify more candidates and sensitize resistant alleles by targeting WT-RAS processing. This potentially could increase the number of patients with EGFR inhibitors that currently cannot receive this therapy.