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Nat Commun. 2018 Dec 4;9(1):5154. doi: 10.1038/s41467-018-07644-6.

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

Author information

1
Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA.
2
Department of Surgery, University of Florida, Gainesville, FL, 32610, USA.
3
Department of Global Health and Center for Drug Discovery and Innovation, University of South Florida, Tampa, FL, 33612, USA.
4
Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA. Said.Sebti@moffitt.org.
5
Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA. Said.Sebti@moffitt.org.

Abstract

Mutant KRas is a significant driver of human oncogenesis and confers resistance to therapy, underscoring the need to develop approaches that disable mutant KRas-driven tumors. Because targeting KRas directly has proven difficult, identifying vulnerabilities specific for mutant KRas tumors is an important alternative approach. Here we show that glycogen synthase kinase 3 (GSK3) is required for the in vitro and in vivo growth and survival of human mutant KRas-dependent tumors but is dispensable for mutant KRas-independent tumors. Further, inhibiting phosphorylation of GSK3 substrates c-Myc on T58 and β-catenin on S33/S37/T41 and their subsequent upregulation contribute to the antitumor activity of GSK3 inhibition. Importantly, GSK3 blockade inhibits the in vivo growth of G12D, G12V, and G12C mutant KRas primary and metastatic patient-derived xenografts from pancreatic cancer patients who progressed on chemo- and radiation therapies. This discovery opens new avenues to target mutant KRas-dependent cancers.

PMID:
30514931
PMCID:
PMC6279809
DOI:
10.1038/s41467-018-07644-6
[Indexed for MEDLINE]
Free PMC Article

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