2. Academic Validation
  3. Cells Lacking the RB1 Tumor Suppressor Gene Are Hyperdependent on Aurora B Kinase for Survival

Cells Lacking the RB1 Tumor Suppressor Gene Are Hyperdependent on Aurora B Kinase for Survival

  • Cancer Discov. 2019 Feb;9(2):230-247. doi: 10.1158/2159-8290.CD-18-0389.
Matthew G Oser 1 2 3,  Raquel Fonseca 1,  Abhishek A Chakraborty 1 3,  Rachel Brough 4 5,  Alexander Spektor 6 7 8,  Rebecca B Jennings 9,  Abdallah Flaifel 9,  Jesse S Novak 9,  Aditi Gulati 4 5,  Elizabeth Buss 1 6,  Scott T Younger 10,  Samuel K McBrayer 1,  Glenn S Cowley 10,  Dennis M Bonal 11,  Quang-De Nguyen 11,  Laura Brulle-Soumare 12,  Paula Taylor 13,  Stefano Cairo 12,  Colm J Ryan 14,  Elizabeth J Pease 15,  Kim Maratea 16,  Jon Travers 13,  David E Root 10,  Sabina Signoretti 1 9,  David Pellman 6 7,  Susan Ashton 13,  Christopher J Lord 4 5,  Simon T Barry 17,  William G Kaelin Jr 18 3 6 10
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
  • 2 Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 3 Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
  • 4 The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, United Kingdom.
  • 5 Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
  • 6 Howard Hughes Medical Institute, Chevy Chase, Maryland.
  • 7 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts.
  • 8 Department of Radiation Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 9 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
  • 10 Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
  • 11 Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 12 XenTech, Genopole, France.
  • 13 IMED Oncology, AstraZeneca, Cheshire, United Kingdom.
  • 14 Systems Biology Ireland, University College Dublin, Dublin, Republic of Ireland.
  • 15 IMED Discovery Sciences, AstraZeneca, Cambridge, United Kingdom.
  • 16 IMED Drug Safety and Metabolism, AstraZeneca, Boston, Massachusetts.
  • 17 IMED Oncology, AstraZeneca, Cambridge, United Kingdom.
  • 18 Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. William_Kaelin@dfci.harvard.edu.
PMID: 30373918 DOI: 10.1158/2159-8290.CD-18-0389
Abstract

Small cell lung Cancer (SCLC) accounts for 15% of lung cancers and is almost always linked to inactivating RB1 and TP53 mutations. SCLC frequently responds, albeit briefly, to chemotherapy. The canonical function of the RB1 gene product RB1 is to repress the E2F transcription factor family. RB1 also plays both E2F-dependent and E2F-independent mitotic roles. We performed a synthetic lethal CRISPR/Cas9 screen in an RB1 -/- SCLC cell line that conditionally expresses RB1 to identify dependencies that are caused by RB1 loss and discovered that RB1 -/- SCLC cell lines are hyperdependent on multiple proteins linked to chromosomal segregation, including Aurora B kinase. Moreover, we show that an Aurora B kinase inhibitor is efficacious in multiple preclinical SCLC models at concentrations that are well tolerated in mice. These results suggest that RB1 loss is a predictive biomarker for sensitivity to Aurora B kinase inhibitors in SCLC and perhaps Other RB1 -/- cancers. SIGNIFICANCE: SCLC is rarely associated with actionable protooncogene mutations. We did a CRISPR/Cas9-based screen that showed that RB1 -/- SCLC are hyperdependent on AURKB, likely because both genes control mitotic fidelity, and confirmed that Aurora B kinase inhibitors are efficacious against RB1 -/- SCLC tumors in mice at nontoxic doses.See related commentary by Dick and Li, p. 169.This article is highlighted in the In This Issue feature, p. 151.

Figures
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