A functional measurement of MAPK pathway activation to predict response to MEK inhibitors in RAS-mutated patients.

Abstract

3071 Background: MEK inhibitors can be used to treat patients with mutations that affect the MAPK pathway. Several MEK inhibitors are currently FDA-approved and effectively treat BRAF-mutated tumors, but RAS-mutated cancers are considered more resistant. However, it is unclear how the many distinct RAS variants impact the MAPK pathway and are affected by MEK inhibitors. We hypothesized that the level of MAPK pathway activation induced by different RAS mutations may predict response to MEK inhibition. Methods: Thirteen RAS mutations from 34 patients treated with MEK inhibitors at UCSD were synthesized, expressed in a HeLa-derived cell line and analyzed in vitro using a functional mutational analysis assay based on assessing downstream reporters in order to measure the activity of these mutations on the MAPK pathway. Each mutation received an activity score based on known oncogenic RAS mutation. Results: The most common type of cancer was colorectal cancer (N = 13). All patients received the MEK inhibitor, trametinib, based therapy. Patients were stratified into two groups: above an activity score of 1 (14 pts) or below it (20 pts). Median progression-free survival (PFS) after MEK inhibitor treatment correlated with higher MAPK activity score (9 vs 3 months; P = 0.041). Conclusions: Using a novel functional assay methodology for characterization of MAPK activation, we show that various RAS mutations activate the MAPK pathway to different levels. Higher activity is associated with longer PFS after MEK inhibitor treatment, suggesting that the relationship between signal transduction strength and clinical relevance merits additional exploration.