Classical RAS proteins are not essential for paradoxical ERK activation induced by RAF inhibitors

Significance RAF inhibitors unexpectedly induce ERK activation in normal and oncogenic RAS tumor cells, making them unsuitable for treating RAS-driven cancers. The precise mechanism of this paradox is not fully understood but is believed to be RAS dependent. In this study, we discovered that classical RAS proteins are not essential for RAF inhibitor-induced ERK activation in H/N/KRAS-less mouse embryonic fibroblasts. We further showed that the MRAS/SHOC2 complex is required for the classical RAS-independent paradoxical ERK activation. Our findings provide new insights into the mechanism of paradoxical ERK activation by RAF inhibitors, and they have important therapeutic implications for developing effective RAF inhibitors.