TEAD Inhibitors Sensitize KRAS^G12C Inhibitors via Dual Cell Cycle Arrest in KRAS^G12C-Mutant NSCLC

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• KRAS^G12C mutations are common in non-small cell lung cancer (NSCLC) and associated with poor prognosis.
• While KRAS^G12C inhibitors offer a breakthrough, therapeutic resistance is a growing challenge.
• YAP1/TAZ-TEAD pathway activity is implicated in resistance to targeted cancer therapies.

Purpose of the Study:

• To investigate the efficacy of combining TEAD inhibitors with KRAS^G12C inhibitors in KRAS^G12C-mutant NSCLC.
• To elucidate the underlying mechanisms of this combination therapy in preclinical models.

Main Methods:

• Utilized in vitro and in vivo models of KRAS^G12C-mutant NSCLC.
• Assessed the anti-tumor efficacy of single-agent TEAD inhibitors versus combination therapy.
• Analyzed molecular changes including gene expression signatures (MYC, E2F) and cell cycle progression.

Main Results:

• TEAD inhibitors alone showed minimal activity in KRAS^G12C-mutant NSCLC cells.
• Combination therapy significantly enhanced the anti-tumor efficacy of KRAS^G12C inhibitors.
• Dual inhibition led to downregulation of MYC/E2F signatures and altered cell cycle distribution, favoring G1 arrest.

Conclusions:

• Co-inhibition of KRAS^G12C and TEAD pathways represents a promising strategy for overcoming resistance in NSCLC.
• This combination induces a dual cell cycle arrest, offering a novel therapeutic approach for KRAS^G12C-mutant NSCLC.