In situ RAS:RAF binding correlates with response to KRASG12C inhibitors in KRASG12C-mutant non–small cell lung cancer
Abstract. Purpose: Therapeutic efficacy of KRASG12C(OFF) inhibitors (KRASG12Ci) in KRASG12C-mutant non–small cell lung cancer (NSCLC) varies widely. The activation status of RAS signaling in tumors with KRASG12C mutation remains unclear, as its ability to cycle between the active GTP-bound and inactive GDP-bound states may influence downstream pathway activation and therapeutic responses. We hypothesized that the interaction between RAS and its downstream effector RAF in tumors may serve as indicators of RAS activity, rendering NSCLC tumors with a high degree of RAS engagement and downstream effects more responsive to KRASG12Ci compared to tumors with lower RAS–RAF interaction. Experimental Design: We developed a method for measuring in situ RAS binding to RAF in cancer samples using proximity ligation assays (PLAs) designed to detect panRAS–CRAF interactions. Results: The panRAS–CRAF PLA signal correlated with levels of both RAS-GTP and phosphorylated ERK protein, suggesting that th
