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Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRASG12C Inhibitor Efficacy
Suman Mukhopadhyay1, Hsin-Yi Huang1, Ziyan Lin2
1Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, NYU Langone Health, New York, New York.
Cancer Research
|September 20, 2023
Summary
Researchers identified synthetic lethal genes that can enhance KRASG12C inhibitor efficacy in non-small cell lung cancer (NSCLC). This discovery offers new therapeutic strategies for difficult-to-treat KRAS-mutant NSCLC, particularly those with STK11/KEAP1 mutations.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Non-small cell lung cancer (NSCLC) frequently harbors KRAS mutations, with KRASG12C being common.
- KRAS-mutant NSCLC with STK11/KEAP1 comutations shows resistance to current therapies.
- KRASG12C inhibitors (G12Ci) offer therapeutic advances, but resistance remains a challenge.
Purpose of the Study:
- To identify genes whose deletion enhances the efficacy of KRASG12C inhibitors (G12Ci) in KRAS/STK11-mutant NSCLC.
- To explore combination strategies to overcome resistance to G12Ci therapy.
- To validate identified synthetic lethal (SL) pathways and their therapeutic potential.
Main Methods:
- Genome-wide CRISPR/Cas9 screening was performed on KRAS/STK11-mutant NSCLC cell lines.
- Synthetic lethal genes were identified and validated using siRNA/shRNA.
- In vitro and in vivo (mouse models) experiments were used to validate the YAP/TAZ/TEAD pathway.
Main Results:
- Genome-wide screens identified recurrent, targetable synthetic lethal genes, including kinases and YAP/TAZ/TEAD pathway components.
- Validation confirmed the role of several SL genes and extensively characterized the YAP/TAZ/TEAD pathway.
- G12Ci treatment induced RHOA activation and ROCK-dependent YAP nuclear translocation.
- Resistant tumors in mice and patients showed overlap with identified SL pathways.
Conclusions:
- The study provides a comprehensive landscape of synthetic lethal targets for combination therapies in KRAS-mutant NSCLC.
- Targeting identified SL genes, particularly the YAP/TAZ/TEAD pathway, may overcome resistance to KRASG12C inhibitors.
- These findings offer a roadmap for developing novel combination strategies for NSCLC treatment.
