Genetic mechanisms of resistance to targeted KRAS inhibition

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• KRAS mutations are key drivers in non-small cell lung cancer (NSCLC).
• Therapeutic resistance to KRAS inhibitors in NSCLC remains a significant challenge.
• Understanding resistance mechanisms is crucial for developing effective treatments.

Purpose of the Study:

• To systematically map resistance mutations to distinct KRAS-targeted therapies using CRISPR base editing screens.
• To identify common and compound-selective resistance mutations in KRAS and other cancer-associated genes.
• To investigate novel strategies for overcoming therapeutic resistance.

Main Methods:

• High-throughput CRISPR base editing screens were employed.
• Saturation KRAS tiling and cancer-associated mutation libraries were utilized.
• In vitro and in vivo models were used to validate findings.

Main Results:

• Common and compound-selective second-site resistance mutations in KRAS were identified.
• Gain-of-function and loss-of-function variants in other genes were found to rewire signaling networks.
• A recurrent Capicua (CIC) mutation conferring resistance to RMC-7977 was discovered.
• Targeting NFκB signaling resensitized CIC-mutant cells to RAS pathway inhibition.

Conclusions:

• CRISPR screens effectively identified mechanisms of resistance to KRAS inhibitors.
• CIC mutations represent a novel mechanism of resistance to specific RAS(ON) inhibitors.
• Targeting NFκB signaling offers a potential strategy to overcome resistance in CIC-mutant NSCLC.