KRAS G12C NSCLC Models Are Sensitive to Direct Targeting of KRAS in Combination with PI3K Inhibition

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• KRAS-mutant lung cancers are challenging to treat.
• Targeting the KRAS p.G12C allele with covalent inhibitors offers specific cancer cell inhibition.
• Intrinsic resistance mechanisms can limit the effectiveness of KRAS G12C inhibitors.

Purpose of the Study:

• To evaluate the response of KRAS G12C-mutant non-small cell lung cancer (NSCLC) models to a second-generation KRAS G12C inhibitor, ARS1620.
• To identify resistance mechanisms to direct KRAS inhibition.
• To discover effective combination strategies to enhance ARS1620 efficacy.

Main Methods:

• Tested ARS1620 in vitro and in vivo on NSCLC models with KRAS G12C mutations.
• Analyzed KRAS downstream signaling to understand differential responses.
• Conducted high-throughput drug screening to identify combination partners for ARS1620.
• Validated promising combinations in vitro, in vivo, and in patient-derived xenografts.

Main Results:

• Response to ARS1620 was heterogeneous across models.
• Adaptive resistance involved MAPK reactivation and failed PI3K-AKT inactivation.
• PI3K-AKT-mTOR pathway inhibitors broadly sensitized models to ARS1620.
• The combination of KRAS G12C inhibitors (G12Ci) and PI3K inhibitors (PI3Ki) showed efficacy in resistant models.

Conclusions:

• Signaling adaptation can limit ARS1620 efficacy in KRAS-mutant NSCLC.
• Combining PI3K inhibitors with KRAS G12C inhibitors can overcome resistance mechanisms.
• This combination strategy holds promise for improving treatment outcomes.