Targeting KRAS codon 13 mutations using direct combination approaches in non-small cell lung cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Direct KRASG12C inhibitors are standard for KRASG12C-mutant non-small cell lung cancer (NSCLC).
• Molecular mechanisms and treatment vulnerabilities of KRAS codon 13 mutations in NSCLC remain less understood.
• KRAS mutations are key drivers in various cancers, including NSCLC.

Purpose of the Study:

• To characterize the tumorigenic properties and vulnerabilities of KRASG13X-mutant NSCLC.
• To evaluate the efficacy of a novel RAS(ON) G13C-selective inhibitor, RMC-8839.
• To identify effective combination therapies for KRASG13X NSCLC.

Main Methods:

• Analysis of a large multi-national cohort of NSCLC patients with KRASG13X mutations.
• Characterization of preclinical models of KRASG13X NSCLC.
• Drug repurposing screen to identify combination partners for RMC-8839.

Main Results:

• KRASG13C and KRASG13D mutations exhibited reduced oncopotency compared to KRASG12C.
• Identified co-mutations in KRASG13X NSCLC, including KEAP1, STK11, BRAF, and NF1.
• RMC-8839 showed reduced viability in KRASG13C NSCLC models; chemotherapy enhanced its efficacy.
• Combination of docetaxel and RMC-8839 demonstrated significant anti-proliferative activity in vitro and in vivo.

Conclusions:

• KRASG13X NSCLC presents distinct biological characteristics and vulnerabilities compared to KRASG12C.
• Novel RAS(ON) G13C-selective inhibitors like RMC-8839 show promise.
• Chemotherapy, specifically docetaxel, is a viable combination partner to enhance RMC-8839 efficacy in KRASG13C-driven NSCLC.