Your browser doesn't support javascript.
loading
Genome-Wide CRISPR Screen Identifies KEAP1 Perturbation as a Vulnerability of ARID1A-Deficient Cells.
Fournier, Louis-Alexandre; Kalantari, Forouh; Wells, James P; Lee, Joon Seon; Trigo-Gonzalez, Genny; Moksa, Michelle M; Smith, Theodore; White, Justin; Shanks, Alynn; Wang, Siyun L; Su, Edmund; Wang, Yemin; Huntsman, David G; Hirst, Martin; Stirling, Peter C.
Afiliación
  • Fournier LA; Terry Fox Laboratory, BC Cancer, Vancouver, BC V5L1Z3, Canada.
  • Kalantari F; Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC V5L1Z3, Canada.
  • Wells JP; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T1Z4, Canada.
  • Lee JS; Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, BC V5L1Z3, Canada.
  • Trigo-Gonzalez G; Terry Fox Laboratory, BC Cancer, Vancouver, BC V5L1Z3, Canada.
  • Moksa MM; Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T1Z4, Canada.
  • Smith T; Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, BC V5L1Z3, Canada.
  • White J; Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T1Z4, Canada.
  • Shanks A; Terry Fox Laboratory, BC Cancer, Vancouver, BC V5L1Z3, Canada.
  • Wang SL; Terry Fox Laboratory, BC Cancer, Vancouver, BC V5L1Z3, Canada.
  • Su E; Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T1Z4, Canada.
  • Wang Y; Terry Fox Laboratory, BC Cancer, Vancouver, BC V5L1Z3, Canada.
  • Huntsman DG; Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T1Z4, Canada.
  • Hirst M; Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T1Z4, Canada.
  • Stirling PC; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T1Z4, Canada.
Cancers (Basel) ; 16(17)2024 Aug 24.
Article en En | MEDLINE | ID: mdl-39272807
ABSTRACT
ARID1A is the core DNA-binding subunit of the BAF chromatin remodeling complex and is mutated in about 8% of all cancers. The frequency of ARID1A loss varies between cancer subtypes, with clear cell ovarian carcinoma (CCOC) presenting the highest incidence at > 50% of cases. Despite a growing understanding of the consequences of ARID1A loss in cancer, there remains limited targeted therapeutic options for ARID1A-deficient cancers. Using a genome-wide CRISPR screening approach, we identify KEAP1 as a genetic dependency of ARID1A in CCOC. Depletion or chemical perturbation of KEAP1 results in selective growth inhibition of ARID1A-KO cell lines and edited primary endometrial epithelial cells. While we confirm that KEAP1-NRF2 signalling is dysregulated in ARID1A-KO cells, we suggest that this synthetic lethality is not due to aberrant NRF2 signalling. Rather, we find that KEAP1 perturbation exacerbates genome instability phenotypes associated with ARID1A deficiency. Together, our findings identify a potentially novel synthetic lethal interaction of ARID1A-deficient cells.
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Cancers (Basel) Año: 2024 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Suiza
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Cancers (Basel) Año: 2024 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Suiza