ABSTRACT: The clinical benefit benefit of small-molecule inhibitors targeting the MAPK pathway depends on achieving greater pathway inhibition in tumors than in normal tissues, thereby maintaining a high therapeutic index (TI). Selective BRAF inhibitors (BRAFis), developed to inhibit BRAF monomer–mediated signaling downstream of RAS, have shown activity in BRAF-mutant tumors, and combinations with MEK inhibitors (MEKis) administered at their maximum tolerated doses (MTD) have been clinically successful. Next-generation pan-RAF inhibitors (pan-RAFis), developed to inhibit RAF dimer–mediated signaling downstream of RAS, have shown activity in RAS-mutant (RAS-MUT) tumors as single agents. However, combining pan-RAFis with MEKis requires dose reductions due to toxicity, resulting in limited clinical benefit. We find that this toxicity stems from MEK inhibition relieving feedback, which enhances RAF activation and pan-RAFi binding in normal cells, driving excessive MAPK suppression and narrowing the TI. Across preclinical studies and clinical trials, such regimens have reached a “therapeutic ceiling” defined by predominant stable disease and only rare regressions. RAF/MEK glues represent a new class of MEK inhibitors that stabilize RAF–MEK complexes and suppress RAF activity. While structural studies have shown these glues bound to both active and inactive RAF conformations, we demonstrate that their inactivating function arises from a biochemical mechanism of spatial trapping: MEK is constitutively cytosolic, and RAF/MEK glues retain RAF in the cytosol, preventing its membrane recruitment and dimerization required for activation. Consistent with this model, in RAS(MUT) models from various tumor types, the RAF/MEK glue avutometinib, when combined with a pan-RAFi, was tolerated at full dose and, importantly, induced tumor regressions, including achieving a 90% overall response rate (ORR) compared to 0% with a conventional pan-RAFi + MEKi regimen in an insensitive KRAS(MUT) model. Tumor regression correlated with deeper MAPK suppression by pharmacodynamic and transcriptional readouts, without evidence of added toxicity. These findings uncover a previously unrecognized mechanism of RAF inactivation by RAF/MEK glues and demonstrate that replacing the MEKi with a RAF/MEK glue can overcome the “therapeutic ceiling” of current MAPK-targeting therapies, shifting outcomes from predominantly stable disease to frequent tumor regressions. More broadly, this work introduces drug-induced proximity as a strategy to reprogram the spatial and biochemical state of wild-type effectors, thereby expanding the therapeutic window for oncogenic pathway-directed therapies and providing a paradigm shift in precision oncology.
