Recent Developments, Challenges and Opportunities in Targeting the KRAS Pathway

KRAS is a highly mutated gene among cancers, especially in the lung, pancreatic and colorectal cancers (CRC). Despite extensive efforts in the past three decades, KRAS remains undruggable. But lately, inhibitors selectively binding to cysteine mutant at 12^thposition (G12C) are in clinical trials as a single agent and in combination with other drugs. FDA approved LUMAKRAS (Sotorasib, AMG510) for metastatic NSCLC, while Adagrasib (MRTX849) is under clinical trials, and it is showing good safety and efficacy in pancreatic and GI tumors. Both these molecules demonstrated better response in NSCLC but have less efficacy in colorectal and other solid cancers. Among non-G12C KRAS mutant cancers, promising data are emerging from G12D inhibition. This review covers the status of KRAS G12C, non- G12C inhibitors, and discusses different nodal proteins in the RAS signaling pathway, mechanism of resistance in targeted therapy and combination approaches. Ongoing clinical trials with G12C inhibitors have promising results. However, a combination of KRAS inhibition with other inhibitors of signaling components in vertical axis (SHP2, SOS1, MEK, PI3K/AKT and EGFR inhibitors) might be beneficial for durable clinical response. Sotorasib in combination with MEK inhibitor showed promising results in preclinical xenograft and PDx models of KRAS mutated cancers. Although at a preclinical stage, other approaches like Tri complex inhibitor, KRAS (ON) inhibitors, and non-G12C inhibitors are of significant interest in KRAS drug discovery. Multiple targeted approaches are being explored based on tumor specific gene expression profiles considering dynamic nature of KRAS activity and heterogeneity of hard to treat tumors.