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.
No external funding was received for this work.
Animal experimentation: All animal work was performed in accordance with Novartis Animal Care and Use Committee (ACUC) regulations and guidelines (reference number 120137). All animals were allowed to acclimate in the Novartis animal facility with access to food and water ad libitum for 3 days prior to manipulation. All cell lines were confirmed as mycoplasma- and rodent pathogens-negative (IMPACT VIII PCR Profile, IDEXX) before implantation.
- William C. Hahn, Dana-Farber Cancer Institue, United States
- Received: July 16, 2019
- Accepted: November 4, 2019
- Accepted Manuscript published: November 19, 2019 (version 1)
© 2019, Zeng et al.
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