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CRISPR screens reveal YAP/TEAD axis as a mediator of drug-tolerant cells in EGFR-mutant NSCLCYusuf, MuhammedCRISPR screensEGFR-mutant lung cancerHippo signaling pathwayOsimertinib resistancePersister cellsDespite initial responses, most patients with metastatic lung cancer—including those with EGFR mutations—ultimately develop resistance to targeted therapies. To systematically uncover mechanisms underlying this resistance, genome-wide CRISPR knockout and activation screens were conducted in EGFR-mutant lung cancer cell lines treated with EGFR inhibitors such as osimertinib and gefitinib. These screens highlighted a recurrent involvement of genes associated with the Hippo signaling pathway. Notably, a subset of tumor cells, termed 'persister' cells, survive initial osimertinib exposure by engaging non-genetic, transcriptional adaptation mechanisms that promote drug tolerance. Our studies, integrating both genetic and pharmacological approaches, identified Hippo pathway activation as a key driver of this drug-tolerant state. Importantly, co-inhibition of EGFR and the Hippo signaling axis led to a pronounced reduction in cell viability in both established cell lines and patient-derived organoids. These findings propose that dual targeting of EGFR and Hippo signaling may offer a promising therapeutic approach to overcome resistance in EGFR-mutant lung cancer.Springer Science and Business Media Deutschland GmbH2026Articlehttps://rdlopen.rawdatalibrary.net/r/kostu/10651https://doi.org/10.1007/s00210-025-04665-z0028-1298enNaunyn-Schmiedeberg's Archives of Pharmacologyinfo:eu-repo/semantics/openAccessinfo:eu-repo/semantics/articlehttps://kostu-rdlopen.rawdatalibrary.net/tr/items/kostu/10651