Abstract
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.
Article and author information
Author details
Funding
No external funding was received for this work.
Ethics
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.
Reviewing Editor
- William C. Hahn, Dana-Farber Cancer Institue, United States
Publication history
- Received: July 16, 2019
- Accepted: November 4, 2019
- Accepted Manuscript published: November 19, 2019 (version 1)
- Version of Record published: December 23, 2019 (version 2)
Copyright
© 2019, Zeng et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 4,479
- Page views
-
- 697
- Downloads
-
- 2
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.
