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GSK3 suppression upregulates β-catenin and c-Myc to abrogate KRas-dependent tumors

Aslamuzzaman Kazi1, Shengyan Xiang1, Hua Yang1

  • 1Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA.

Nature Communications
|December 6, 2018
PubMed

Insights

Targeting glycogen synthase kinase 3 (GSK3) effectively inhibits mutant KRas-driven cancers, including pancreatic tumors resistant to standard therapies. This approach offers a new strategy for treating these aggressive cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Mutant KRas drives human oncogenesis and therapy resistance.
  • Directly targeting KRas is challenging, necessitating alternative strategies.
  • Identifying vulnerabilities specific to mutant KRas tumors is crucial.

Purpose of the Study:

  • To investigate the role of glycogen synthase kinase 3 (GSK3) in mutant KRas-dependent tumors.
  • To determine if GSK3 inhibition can serve as a therapeutic strategy against mutant KRas cancers.
  • To elucidate the mechanisms underlying GSK3 inhibition's antitumor activity.

Main Methods:

  • Assessed GSK3 requirement for mutant KRas tumor growth in vitro and in vivo.
  • Investigated the impact of GSK3 inhibition on phosphorylation of c-Myc and β-catenin.
  • Evaluated GSK3 blockade in patient-derived xenografts from pancreatic cancer patients.

Main Results:

  • GSK3 is essential for mutant KRas-dependent tumor growth and survival.
  • GSK3 inhibition reduces phosphorylation of c-Myc and β-catenin, leading to their upregulation.
  • GSK3 blockade effectively inhibited in vivo growth of diverse mutant KRas pancreatic cancer xenografts, including therapy-resistant cases.

Conclusions:

  • GSK3 is a critical vulnerability in mutant KRas-driven cancers.
  • Inhibition of GSK3 demonstrates significant antitumor activity against therapy-resistant mutant KRas tumors.
  • Targeting GSK3 presents a promising new therapeutic avenue for mutant KRas-dependent cancers.

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