sotorasib + palbociclib

Sotorasib + palbociclib is an investigational combination therapy consisting of two small molecule inhibitors: sotorasib, a covalent KRAS G12C inhibitor approved for KRAS G12C-mutant non-small cell lung cancer, and palbociclib, an oral selective inhibitor of cyclin-dependent kinase 4/6 (CDK4/6), approved for hormone receptor-positive advanced breast cancer. Sotorasib irreversibly binds to the KRAS G12C mutant protein, locking it in the inactive GDP-bound conformation and thereby inhibiting downstream signaling in the MAPK pathway. Palbociclib inhibits CDK4 and CDK6, preventing phosphorylation of the retinoblastoma protein and blocking cell cycle progression from G1 to S phase. The combination is under clinical investigation for synergistic effects in KRAS G12C-mutant non-small cell lung cancer (NSCLC) and potentially other solid tumors.