ArticleCancer research2023
Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRASG12C Inhibitor Efficacy.
Article in Cancer research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 86 papers.
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Who cites it
86 citing papers in PubMed, 99 citations in OpenAlex.
- YAP/TEAD inhibitor VT3989 in solid tumors: a phase 1/2 trial.Nature medicine · 2025Trial
- CRISPR-cas systems in pharmacology: functional pharmacogenomics, drug screening, resistance, and therapeutic translation.Functional & integrative genomics · 2026Review
- Overcoming Resistance: Targeting Survivin-Driven Apoptotic Resistance Restores Irinotecan Sensitivity inCancers · 2026Article
- Targeting β-Adrenergic Signaling in Colorectal Cancer: Molecular Mechanisms and Therapeutic Potential of β-Blockers.Cancers · 2026Review
- Pharmacologic Resistance in Soft Tissue Sarcomas: Mechanisms, Biomarkers, and Translational Therapeutic Strategies.Cancers · 2026Review
- Macrophage Polarization as a Target for Colorectal Cancer Treatment Optimization: A Systematic Review.Cancers · 2026Review
- Identification of β-Lapachone as a Potent USP22 Inhibitor That Suppresses Cancer Stemness and Enhances Chemosensitivity in Lung Adenocarcinoma.International journal of molecular sciences · 2026Article
- EZH2 as regulator of stemness signature and driver of esophageal squamous cell carcinomas.Scientific reports · 2026Article
- Toosendanin suppresses acute myeloid leukemia by targeting DDX5/c-Myc axis to inhibit protein synthesis.Journal of translational medicine · 2026Article
- Mitochondrial Metabolic Reprogramming in Colorectal Cancer-Associated Fibroblasts: An Up-to-Date Review.Cancers · 2026Review
- CircPRKCA Promotes NSCLC Progression via miR-200b-3p/FRMD6/SNAI2 Axis.International journal of molecular sciences · 2026Article
- Review
- Tolerance and Resistance to Targeted Therapy in NSCLC: Emerging Concepts and Strategies.JTO clinical and research reports · 2026Review
- Lactylation and acetylation: parallel paths, divergent deeds, and research dilemmas.Journal of translational medicine · 2026Review
- Dictamnine Inhibits WNT Pathway and EMT Progression in Prostate Cancer and Remodels the Tumor Microenvironment.Cancers · 2026Article
- CRISPR-Cas9 Screening Identifies Resistance Mechanisms to KRAS Inhibition in Pancreatic Cancer.Cancer research · 2026Article
- Article
- Isoform-specific single-cell perturb-seq reveals distinct functions of alternative promoters in drug response.Nucleic acids research · 2026Article
- Stromal cells contribute to progression, recurrence, and metastasis in oral squamous cell carcinoma: a call for therapy.Journal of translational medicine · 2026Review
- Effects of N361 Glycosylation on Epidermal Growth Factor Receptor Biological Function.Cancers · 2026Article
26 more citing papers are in PubMed but not listed here.
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Authors and funding
26 authors at 5 institutions in 1 country.
Funding
Abstract
Non-small lung cancers (NSCLC) frequently (∼30%) harbor KRAS driver mutations, half of which are KRASG12C. KRAS-mutant NSCLC with comutated STK11 and/or KEAP1 is particularly refractory to conventional, targeted, and immune therapy. Development of KRASG12C inhibitors (G12Ci) provided a major therapeutic advance, but resistance still limits their efficacy. To identify genes whose deletion augments efficacy of the G12Cis adagrasib (MRTX-849) or adagrasib plus TNO155 (SHP2i), we performed genome-wide CRISPR/Cas9 screens on KRAS/STK11-mutant NSCLC lines. Recurrent, potentially targetable, synthetic lethal (SL) genes were identified, including serine-threonine kinases, tRNA-modifying and proteoglycan synthesis enzymes, and YAP/TAZ/TEAD pathway components. Several SL genes were confirmed by siRNA/shRNA experiments, and the YAP/TAZ/TEAD pathway was extensively validated in vitro and in mice. Mechanistic studies showed that G12Ci treatment induced gene expression of RHO paralogs and activators, increased RHOA activation, and evoked ROCK-dependent nuclear translocation of YAP. Mice and patients with acquired G12Ci- or G12Ci/SHP2i-resistant tumors showed strong overlap with SL pathways, arguing for the relevance of the screen results. These findings provide a landscape of potential targets for future combination strategies, some of which can be tested rapidly in the clinic. SIGNIFICANCE: Identification of synthetic lethal genes with KRASG12C using genome-wide CRISPR/Cas9 screening and credentialing of the ability of TEAD inhibition to enhance KRASG12C efficacy provides a roadmap for combination strategies. See related commentary by Johnson and Haigis, p. 4005.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.