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

Matthew G Oser1,2,3, Raquel Fonseca1, Abhishek A Chakraborty1,3

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Cancer Discovery
|October 31, 2018
PubMed

Insights

Small cell lung cancer cells lacking RB1 show a dependency on Aurora B kinase. Inhibiting this kinase effectively treats RB1-deficient SCLC models, suggesting RB1 loss as a predictive biomarker for Aurora B kinase inhibitors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Small cell lung cancer (SCLC) comprises 15% of lung cancer cases.
  • SCLC is strongly associated with inactivating mutations in RB1 and TP53 tumor suppressor genes.
  • While chemotherapy offers brief responses, SCLC rarely harbors actionable proto-oncogene mutations.

Purpose of the Study:

  • To identify genetic dependencies arising from RB1 loss in SCLC.
  • To explore therapeutic strategies targeting RB1-deficient SCLC.
  • To evaluate Aurora B kinase as a potential therapeutic target in SCLC.

Main Methods:

  • Conducted a synthetic lethal CRISPR/Cas9 screen in an RB1-deficient SCLC cell line.
  • Utilized RB1-conditional SCLC cell lines for screening.
  • Tested Aurora B kinase inhibitors in preclinical SCLC models.

Main Results:

  • RB1-deficient SCLC cell lines exhibit hyperdependence on chromosomal segregation proteins, including Aurora B kinase (AURKB).
  • Aurora B kinase inhibition demonstrated efficacy in multiple preclinical SCLC models.
  • Inhibitor concentrations were well-tolerated in mouse models.

Conclusions:

  • RB1 loss is a potential predictive biomarker for sensitivity to Aurora B kinase inhibitors in SCLC.
  • Targeting Aurora B kinase presents a promising therapeutic avenue for RB1-wildtype SCLC.
  • This study highlights a novel therapeutic vulnerability in RB1-deficient cancers.

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