JAB-3312 + sotorasib

JAB-3312 + sotorasib is an investigational combination therapy composed of JAB-3312, a small molecule allosteric inhibitor of SHP2, and sotorasib, a small molecule covalent inhibitor of KRAS G12C. SHP2 (encoded by PTPN11) is a nonreceptor protein tyrosine phosphatase that mediates receptor tyrosine kinase (RTK) signaling to the RAS/MAPK pathway; its inhibition is proposed to prevent pathway reactivation and resistance to downstream targeted therapies. Sotorasib directly inhibits KRAS G12C, a common oncogenic driver mutation in several cancers, particularly non-small cell lung cancer (NSCLC). Preclinical and early-phase clinical studies with JAB-3312 and KRAS G12C inhibitors (including sotorasib and glecirasib) show synergistic inhibition of tumor growth and downstream ERK signaling in KRAS G12C mutant models and suggest the potential to overcome or delay acquired resistance to KRAS G12C inhibition[1][3][6][7]. This combination is being explored in clinical trials for advanced solid tumors, especially NSCLC harboring KRAS G12C mutations.