Genome-wide CRISPR screens identify the YAP/TEAD axis as a driver of persister cells in EGFR mutant lung cancer.

Humans Lung Neoplasms / genetics ErbB Receptors / genetics Drug Resistance, Neoplasm / genetics Transcription Factors / genetics Mutation Cell Line, Tumor Acrylamides / pharmacology YAP-Signaling Proteins / metabolism Aniline Compounds / pharmacology Gefitinib / pharmacology Hippo Signaling Pathway DNA-Binding Proteins / genetics Adaptor Proteins, Signal Transducing / genetics Signal Transduction TEA Domain Transcription Factors Protein Kinase Inhibitors / pharmacology Antineoplastic Agents / pharmacology Clustered Regularly Interspaced Short Palindromic Repeats CRISPR-Cas Systems Indoles Pyrimidines

Journal

Communications biology

ISSN: 2399-3642

Titre abrégé: Commun Biol

Pays: England

ID NLM: 101719179

Informations de publication

Date de publication:
24 Apr 2024

Historique:

received: 27 01 2023

accepted: 12 04 2024

medline: 25 4 2024

pubmed: 25 4 2024

entrez: 24 4 2024

Statut: epublish

Résumé

Most lung cancer patients with metastatic cancer eventually relapse with drug-resistant disease following treatment and EGFR mutant lung cancer is no exception. Genome-wide CRISPR screens, to either knock out or overexpress all protein-coding genes in cancer cell lines, revealed the landscape of pathways that cause resistance to the EGFR inhibitors osimertinib or gefitinib in EGFR mutant lung cancer. Among the most recurrent resistance genes were those that regulate the Hippo pathway. Following osimertinib treatment a subpopulation of cancer cells are able to survive and over time develop stable resistance. These 'persister' cells can exploit non-genetic (transcriptional) programs that enable cancer cells to survive drug treatment. Using genetic and pharmacologic tools we identified Hippo signalling as an important non-genetic mechanism of cell survival following osimertinib treatment. Further, we show that combinatorial targeting of the Hippo pathway and EGFR is highly effective in EGFR mutant lung cancer cells and patient-derived organoids, suggesting a new therapeutic strategy for EGFR mutant lung cancer patients.

Identifiants

DOI: 10.1038/s42003-024-06190-w PMID: 38658677

pubmed: 38658677

doi: 10.1038/s42003-024-06190-w

pii: 10.1038/s42003-024-06190-w

doi:

Substances chimiques

ErbB Receptors EC 2.7.10.1

EGFR protein, human EC 2.7.10.1

Transcription Factors 0

osimertinib 3C06JJ0Z2O

Acrylamides 0

YAP1 protein, human 0

YAP-Signaling Proteins 0

Aniline Compounds 0

Gefitinib S65743JHBS

DNA-Binding Proteins 0

Adaptor Proteins, Signal Transducing 0

TEA Domain Transcription Factors 0

Protein Kinase Inhibitors 0

Antineoplastic Agents 0

TEAD1 protein, human 0

Indoles 0

Pyrimidines 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

497

Informations de copyright

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