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Integrative oncogene-dependency mapping identifies RIT1 vulnerabilities and synergies in lung cancer.
Vichas, Athea; Riley, Amanda K; Nkinsi, Naomi T; Kamlapurkar, Shriya; Parrish, Phoebe C R; Lo, April; Duke, Fujiko; Chen, Jennifer; Fung, Iris; Watson, Jacqueline; Rees, Matthew; Gabel, Austin M; Thomas, James D; Bradley, Robert K; Lee, John K; Hatch, Emily M; Baine, Marina K; Rekhtman, Natasha; Ladanyi, Marc; Piccioni, Federica; Berger, Alice H.
Afiliação
  • Vichas A; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Riley AK; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Nkinsi NT; Molecular and Cellular Biology Program, University of Washington, Seattle, WA, USA.
  • Kamlapurkar S; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Parrish PCR; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Lo A; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Duke F; Department of Genome Sciences, University of Washington, Seattle, WA, USA.
  • Chen J; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Fung I; Department of Genome Sciences, University of Washington, Seattle, WA, USA.
  • Watson J; Broad Institute of MIT & Harvard, Cambridge, MA, USA.
  • Rees M; Broad Institute of MIT & Harvard, Cambridge, MA, USA.
  • Gabel AM; Broad Institute of MIT & Harvard, Cambridge, MA, USA.
  • Thomas JD; Broad Institute of MIT & Harvard, Cambridge, MA, USA.
  • Bradley RK; Broad Institute of MIT & Harvard, Cambridge, MA, USA.
  • Lee JK; Department of Genome Sciences, University of Washington, Seattle, WA, USA.
  • Hatch EM; Medical Scientist Training Program, University of Washington, Seattle, WA, USA.
  • Baine MK; Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Rekhtman N; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Ladanyi M; Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Piccioni F; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Berger AH; Department of Genome Sciences, University of Washington, Seattle, WA, USA.
Nat Commun ; 12(1): 4789, 2021 08 09.
Article em En | MEDLINE | ID: mdl-34373451
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Oncogenes / Neoplasias Pulmonares Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Oncogenes / Neoplasias Pulmonares Idioma: En Ano de publicação: 2021 Tipo de documento: Article