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

Athea Vichas, Amanda K. Riley, Naomi T. Nkinsi, Shriya Kamlapurkar, Phoebe C. R. Parrish, April Lo, Fujiko Duke, Jennifer Chen, Iris Fung, Jacqueline Watson, Matthew Rees, Austin M. Gabel, James D. Thomas, Robert K. Bradley, John K. Lee, Emily M. Hatch, Marina K. Baine, Natasha Rekhtman, Marc Ladanyi, Federica Piccioni and Alice H. Berger ()
Additional contact information
Athea Vichas: Human Biology Division, Fred Hutchinson Cancer Research Center
Amanda K. Riley: Human Biology Division, Fred Hutchinson Cancer Research Center
Naomi T. Nkinsi: Human Biology Division, Fred Hutchinson Cancer Research Center
Shriya Kamlapurkar: Human Biology Division, Fred Hutchinson Cancer Research Center
Phoebe C. R. Parrish: Human Biology Division, Fred Hutchinson Cancer Research Center
April Lo: Human Biology Division, Fred Hutchinson Cancer Research Center
Fujiko Duke: Broad Institute of MIT & Harvard
Jennifer Chen: Broad Institute of MIT & Harvard
Iris Fung: Broad Institute of MIT & Harvard
Jacqueline Watson: Broad Institute of MIT & Harvard
Matthew Rees: Broad Institute of MIT & Harvard
Austin M. Gabel: University of Washington
James D. Thomas: Fred Hutchinson Cancer Research Center
Robert K. Bradley: University of Washington
John K. Lee: Human Biology Division, Fred Hutchinson Cancer Research Center
Emily M. Hatch: Human Biology Division, Fred Hutchinson Cancer Research Center
Marina K. Baine: Memorial Sloan Kettering Cancer Center
Natasha Rekhtman: Memorial Sloan Kettering Cancer Center
Marc Ladanyi: Memorial Sloan Kettering Cancer Center
Federica Piccioni: Broad Institute of MIT & Harvard
Alice H. Berger: Human Biology Division, Fred Hutchinson Cancer Research Center

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24841-y

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