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RNAi screen reveals synthetic lethality between cyclin G-associated kinase and FBXW7 by inducing aberrant mitoses

Saoirse O Dolly1,2, Mark D Gurden3, Konstantinos Drosopoulos3

  • 1Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.

British Journal of Cancer
|August 23, 2017
PubMed
Abstract

Insights

Researchers identified cyclin G-associated kinase (GAK) as a therapeutic target for F-box and WD40 repeat domain-containing 7 (FBXW7)-deficient cancers. Targeting GAK in FBXW7-deficient cells induces apoptosis, offering a new treatment strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • F-box and WD40 repeat domain-containing 7 (FBXW7) is a tumor suppressor E3 ubiquitin ligase.
  • Loss of FBXW7 function in cancer leads to oncogenic substrate stabilization, promoting proliferation and survival.
  • FBXW7 deficiency is common in many cancers, yet lacks targeted therapies.

Purpose of the Study:

  • To identify novel therapeutic targets for FBXW7-deficient tumors.
  • To explore synthetic lethality in the context of FBXW7 loss.

Main Methods:

  • Conducted a siRNA kinome screen to identify genes synthetically lethal with FBXW7 deficiency.
  • Validated identified hits through further experiments.

Main Results:

  • Identified cyclin G-associated kinase (GAK) as a synthetic lethal partner of FBXW7.
  • Combined FBXW7 and GAK loss induced cell cycle defects, multipolar mitoses, and apoptosis.
  • The synthetic lethality mechanism is independent of GAK's role in endocytosis.

Conclusions:

  • Cyclin G-associated kinase (GAK) represents a potential therapeutic target for FBXW7-deficient cancers.
  • This finding offers a new therapeutic strategy for a wide range of human cancers with limited treatment options.

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