ArticleOncogene2022
Genome-wide CRISPR-cas9 knockout screening identifies GRB7 as a driver for MEK inhibitor resistance in KRAS mutant colon cancer.
Article in Oncogene, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers, 1 of them a synthesis that pooled it.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
51 citing papers in PubMed, 1 synthesis or guideline pooled it, 70 citations in OpenAlex.
- Preclinical Anticipation of On- and Off-Target Resistance Mechanisms to Anti-Cancer Drugs: A Systematic Review.International journal of molecular sciences · 2024Pooled it
- Dihydroartemisinin inhibits mutant KRAS to potentiate regorafenib plus anti-PD-1 in KRAS-mutant colorectal cancer liver metastases.Cell death & disease · 2026Article
- Pooled single-cell screen in colorectal cancer defines transcriptional modules linked to oncogenes.Molecular systems biology · 2026Article
- Targeting PLK1 potentiates the antitumor efficacy of EGFR-TKIs through inhibiting the JAK1/STAT3 pathway.Cell death & disease · 2026Article
- Unravelling Resistance: Integrating Metabolism, Epigenetics, Immunology, and Proteostasis in Strategies against Kirsten Rat Sarcoma Viral Oncogene Homolog-mutant Colorectal Cancer.International journal of biological sciences · 2026Review
- Review
- NAD+-Boosters Improve Mitochondria Quality Control In Parkinson's Disease Models Via Mitochondrial UPR.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Targeting LINC02320 prevents colorectal cancer growth via GRB7-dependent inhibition of MAPK signaling pathway.Cellular & molecular biology letters · 2025Article
- Applications of CRISPR-Cas9 in mitigating cellular senescence and age-related disease progression.Clinical and experimental medicine · 2025Review
- Perturbomics: CRISPR-Cas screening-based functional genomics approach for drug target discovery.Experimental & molecular medicine · 2025Review
- Investigation of the cytotoxic effects and mechanisms of the SLC39A6-targeting ADC drug BRY812 in CRC.Scientific reports · 2025Article
- CRISPR/Cas9 system: a novel approach to overcome chemotherapy and radiotherapy resistance in cancer.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- Accelerating discovery of bioactive ligands with pharmacophore-informed generative models.Nature communications · 2025Article
- Mitochondrial signatures shape phenotype switching and apoptosis in response to PLK1 inhibitors.Life science alliance · 2025Article
- Mechanisms and Strategies to Overcome Drug Resistance in Colorectal Cancer.International journal of molecular sciences · 2025Review
- Construction of a Prognostic Model based on CSC-related Genes in Patients with Colorectal Cancer.Journal of Cancer · 2025Article
- PLK1 Mediates the Proliferation and Contraction of Airway Smooth Muscle Cells and Has a Role in T2-High Asthma with Neutrophilic Inflammation Model.Journal of inflammation research · 2025Article
- YAP/TAZ mediates resistance to KRAS inhibitors through inhibiting proapoptosis and activating the SLC7A5/mTOR axis.JCI insight · 2024Article
- Elucidating the role of CYFIP2 in conferring cisplatin resistance in esophageal squamous cell carcinoma.Scientific reports · 2024Article
- Signaling pathways involved in colorectal cancer: pathogenesis and targeted therapy.Signal transduction and targeted therapy · 2024Review
Corrections and comments
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Authors and funding
14 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Targeting the KRAS pathway is a promising but challenging approach for colorectal cancer therapy. Despite showing potent efficacy in BRAF-mutated melanoma, MEK inhibitors appeared to be tolerated by colorectal cancer cells due to their intrinsic compensatory signaling. Here, we performed genome-wide CRISPR/Cas9 screening in the presence of MEK inhibitor to identify genes that are synthetically lethal with MEK inhibition in CRC models harboring KRAS mutations. Several genes were identified as potential functional drivers, which were significantly enriched in the GRB7-mediated RTK pathway. Loss-of-function and gain-of-function assays validated that GRB7 potently rendered CRC cells primary resistance to MEK inhibitors through the RTK pathway. Mass spectrum analysis of GRB7 immunoprecipitates revealed that PLK1 was the predominant interacting kinase of GRB7. Inhibition of PLK1 suppressed downstream signaling of RTK, including FAK, STAT3, AKT, and 4EBP1. The combination of PLK1 and MEK inhibitors synergistically inhibited CRC cell proliferation and induced apoptosis in vitro and in vivo. In conclusion, we identified GRB7-PLK1 as a pivotal axis mediating RTKs, resulting in MEK inhibitor tolerance. PLK1 is therefore a promising target for synergizing MEK inhibitors in the clinical treatment of CRC patients harboring KRAS mutations.
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