KRAS G12C inhibitor combination therapies: current evidence and challenge

Abstract

Although KRAS G12C inhibitors have proven that KRAS is a "druggable" target of cancer, KRAS G12C inhibitor monotherapies have demonstrated limited clinical efficacy due to primary and acquired resistance mechanisms. Multiple combinations of KRAS G12C inhibitors with other targeted therapies, such as RTK, SHP2, and MEK inhibitors, have been investigated in clinical trials to overcome the resistance. They have demonstrated promising efficacy especially by combining KRAS G12C and EGFR inhibitors for KRAS G12C-mutated colorectal cancer. Many clinical trials of combinations of KRAS G12C inhibitors with other targeted therapies, such as SOS1, ERK, CDK4/6, and wild-type RAS, are ongoing. Furthermore, preclinical data have suggested additional promising KRAS G12C combinations with YAP/TAZ-TEAD inhibitors, FAK inhibitors, and farnesyltransferase inhibitors. The combinations of KRAS G12C inhibitors with immunotherapies and chemotherapies have also been investigated, and the preliminary results were reported. More recently, KRAS-targeted therapies not limited to KRAS G12C are being developed, potentially broadening the treatment landscape of KRAS-mutated cancers. Rationally combining KRAS inhibitors with other therapeutics is likely to play a significant role in future treatment for KRAS-mutated solid tumors.

Keywords: KRAS; KRAS G12C inhibitors; MAPK; RTK inhibitors; combination (combined) therapy; immunotherapy; mTOR.

Figure 1

KRAS G12C signaling pathways and medications under trial in combination with KRAS G12C inhibitors. The activating and inhibiting signaling are expressed by pointed head and blunt head arrows, respectively. Arrows with broken lines mean a multi-step effect rather than a direct effect. Medications to target KRAS G12C are listed in yellow boxes. Medications in red boxes are being investigated in clinical trials as combination treatments with KRAS G12C inhibitors. Medications in green boxes are not currently in clinical trials but have the potential to be combined with KRAS G12C inhibitors based on preclinical evidence. Created with BioRender.com.