Mechanisms of Resistance to KRAS^G12C Inhibitors

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• KRAS is a common human oncogene, historically considered
• undruggable
• due to difficulties in developing direct inhibitors.
• Recent advancements have led to subtype-specific inhibitors, particularly for KRAS G12C mutations.
• Drugs like adagrasib and sotorasib targeting KRAS G12C have entered clinical trials with early efficacy signals.

Purpose of the Study:

• To review the current evidence for KRAS G12C inhibitors.
• To discuss identified mechanisms of drug resistance to KRAS G12C inhibitors.
• To explore potential strategies and combination therapies to overcome resistance.

Main Methods:

• Literature review of preclinical studies and clinical trials.
• Analysis of resistance mechanisms reported in scientific literature.
• Identification and discussion of potential combination therapy targets.

Main Results:

• KRAS G12C inhibitors demonstrate early clinical efficacy.
• Drug resistance is a significant anticipated limitation for KRAS G12C inhibitors in vivo.
• Several resistance mechanisms have been identified in preclinical studies.

Conclusions:

• KRAS G12C inhibitors represent a significant advancement in targeting oncogenic KRAS.
• Overcoming drug resistance through combination therapies is crucial for sustained clinical benefit.
• Ongoing clinical trials are investigating combination strategies including SHP2, RTKs, downstream effectors, and PD1/PDL1 inhibitors.