sotorasib + everolimus

**sotorasib + everolimus** is an investigational combination therapy composed of two small molecule drugs: - **sotorasib** is a covalent inhibitor of the KRAS G12C mutant protein, approved for KRAS G12C-mutated non-small cell lung cancer (NSCLC). It irreversibly binds the cysteine residue in the switched II pocket of KRAS (G12C), locking it in its inactive (GDP-bound) form and thereby suppressing downstream signaling cascades including MAPK/ERK, resulting in cell cycle arrest and suppressed tumor proliferation[5][6][1]. - **everolimus** is an allosteric inhibitor of mTORC1 (mechanistic target of rapamycin complex 1). It binds to FKBP12 to form a complex that inhibits mTOR, reducing cancer cell growth, proliferation, angiogenesis, and glucose uptake. It is approved for several cancers including renal cell carcinoma, breast cancer, and tuberous sclerosis complex[2][1]. The combination is primarily being explored preclinically as a strategy for KRAS G12C-mutated cancers to overcome resistance mechanisms and expand antitumor efficacy, though preclinical data show that everolimus plus sotorasib resulted in only moderate tumor growth suppression, performing worse than other mTOR inhibitors in combination with sotorasib[1]. Neither the combination nor a co-formulated product is currently approved for any indication.