Integrative oncogene-dependency mapping identifies RIT1 vulnerabilities and synergies in lung cancer Journal Article

   

Authors:	Vichas, A.; Riley, A. K.; Nkinsi, N. T.; Kamlapurkar, S.; Parrish, P. C. R.; Lo, A.; Duke, F.; Chen, J.; Fung, I.; Watson, J.; Rees, M.; Gabel, A. M.; Thomas, J. D.; Bradley, R. K.; Lee, J. K.; Hatch, E. M.; Baine, M. K.; Rekhtman, N.; Ladanyi, M.; Piccioni, F.; Berger, A. H.
Article Title:	Integrative oncogene-dependency mapping identifies RIT1 vulnerabilities and synergies in lung cancer
Abstract:	CRISPR-based cancer dependency maps are accelerating advances in cancer precision medicine, but adequate functional maps are limited to the most common oncogenes. To identify opportunities for therapeutic intervention in other rarer subsets of cancer, we investigate the oncogene-specific dependencies conferred by the lung cancer oncogene, RIT1. Here, genome-wide CRISPR screening in KRAS, EGFR, and RIT1-mutant isogenic lung cancer cells identifies shared and unique vulnerabilities of each oncogene. Combining this genetic data with small-molecule sensitivity profiling, we identify a unique vulnerability of RIT1-mutant cells to loss of spindle assembly checkpoint regulators. Oncogenic RIT1M90I weakens the spindle assembly checkpoint and perturbs mitotic timing, resulting in sensitivity to Aurora A inhibition. In addition, we observe synergy between mutant RIT1 and activation of YAP1 in multiple models and frequent nuclear overexpression of YAP1 in human primary RIT1-mutant lung tumors. These results provide a genome-wide atlas of oncogenic RIT1 functional interactions and identify components of the RAS pathway, spindle assembly checkpoint, and Hippo/YAP1 network as candidate therapeutic targets in RIT1-mutant lung cancer. © 2021, The Author(s).
Journal Title:	Nature Communications
Volume:	12
ISSN:	2041-1723
Publisher:	Nature Publishing Group
Date Published:	2021-08-09
Start Page:	4789
Language:	English
DOI:	10.1038/s41467-021-24841-y
PROVIDER:	scopus
PMCID:	PMC8352964
PUBMED:	34373451
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85112049167&doi=10.1038%2fs41467-021-24841-y&partnerID=40&md5=04a082415be0c455eaa049b3b675d0cb
Notes:	Article -- Export Date: 1 September 2021 -- Source: Scopus

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