1. Genome-wide CRISPR screens identify the YAP/TEAD axis as a driver of persister cells in EGFR mutant lung cancer.
- Author
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Pfeifer M, Brammeld JS, Price S, Pilling J, Bhavsar D, Farcas A, Bateson J, Sundarrajan A, Miragaia RJ, Guan N, Arnold S, Tariq L, Grondine M, Talbot S, Guerriero ML, O'Neill DJ, Young J, Company C, Dunn S, Thorpe H, Martin MJ, Maratea K, Barrell D, Ahdesmaki M, Mettetal JT, Brownell J, and McDermott U
- Subjects
- Humans, Cell Line, Tumor, YAP-Signaling Proteins metabolism, YAP-Signaling Proteins genetics, Aniline Compounds pharmacology, Aniline Compounds therapeutic use, Gefitinib pharmacology, Hippo Signaling Pathway, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing metabolism, Signal Transduction, TEA Domain Transcription Factors, Protein Kinase Inhibitors pharmacology, Antineoplastic Agents pharmacology, Clustered Regularly Interspaced Short Palindromic Repeats, CRISPR-Cas Systems, Lung Neoplasms genetics, Lung Neoplasms drug therapy, Lung Neoplasms metabolism, Lung Neoplasms pathology, ErbB Receptors genetics, ErbB Receptors metabolism, Drug Resistance, Neoplasm genetics, Transcription Factors genetics, Transcription Factors metabolism, Mutation, Acrylamides pharmacology, Acrylamides therapeutic use, Indoles, Pyrimidines
- Abstract
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., (© 2024. The Author(s).)
- Published
- 2024
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