Genome-wide CRISPR screening reveals genetic modifiers of mutant EGFR dependence in human NSCLC.

EGFR-mutant NSCLCs frequently respond to EGFR tyrosine kinase inhibitors (TKIs). However, the responses are not durable, and the magnitude of tumor regression is variable, suggesting the existence of genetic modifiers of EGFR dependency. Here, we applied a genome-wide CRISPR-Cas9 screening to identify genetic determinants of EGFR TKI sensitivity and uncovered ...
putative candidates. We show that knockout of RIC8A, essential for G-alpha protein activation, enhanced EGFR TKI-induced cell death. Mechanistically, we demonstrate that RIC8A is a positive regulator of YAP signaling, activation of which rescued the EGFR TKI sensitizing phenotype resulting from RIC8A knockout. We also show that knockout of ARIH2, or other components in the Cullin-5 E3 complex, conferred resistance to EGFR inhibition, in part by promoting nascent protein synthesis through METAP2. Together, these data uncover a spectrum of previously unidentified regulators of EGFR TKI sensitivity in EGFR-mutant human NSCLC, providing insights into the heterogeneity of EGFR TKI treatment responses.
Mesh Terms:
A549 Cells, Adaptor Proteins, Signal Transducing, Animals, CRISPR-Cas Systems, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Clustered Regularly Interspaced Short Palindromic Repeats, Cullin Proteins, ErbB Receptors, Female, Gene Expression Regulation, Neoplastic, Gene Knockout Techniques, Guanine Nucleotide Exchange Factors, HEK293 Cells, Humans, Methionyl Aminopeptidases, Mice, Mice, Nude, Receptors, Lysophosphatidic Acid, Signal Transduction, Transcription Factors, Transcriptome, Ubiquitin-Protein Ligases, rhoA GTP-Binding Protein
Elife
Date: Dec. 19, 2018
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