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

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  • Aslamuzzaman Kazi

    (H. Lee Moffitt Cancer Center and Research Institute)

  • Shengyan Xiang

    (H. Lee Moffitt Cancer Center and Research Institute)

  • Hua Yang

    (H. Lee Moffitt Cancer Center and Research Institute)

  • Daniel Delitto

    (University of Florida)

  • José Trevino

    (University of Florida)

  • Rays H. Y. Jiang

    (University of South Florida)

  • Muhammad Ayaz

    (H. Lee Moffitt Cancer Center and Research Institute)

  • Harshani R. Lawrence

    (H. Lee Moffitt Cancer Center and Research Institute)

  • Perry Kennedy

    (H. Lee Moffitt Cancer Center and Research Institute)

  • Saïd M. Sebti

    (H. Lee Moffitt Cancer Center and Research Institute
    H. Lee Moffitt Cancer Center and Research Institute)

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.

Suggested Citation

  • Aslamuzzaman Kazi & Shengyan Xiang & Hua Yang & Daniel Delitto & José Trevino & Rays H. Y. Jiang & Muhammad Ayaz & Harshani R. Lawrence & Perry Kennedy & Saïd M. Sebti, 2018. "GSK3 suppression upregulates β-catenin and c-Myc to abrogate KRas-dependent tumors," Nature Communications, Nature, vol. 9(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07644-6
    DOI: 10.1038/s41467-018-07644-6
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    Cited by:

    1. Jun Li & Jie Ma & Qiyu Zhang & Huizi Gong & Dunqin Gao & Yujie Wang & Biyou Li & Xiao Li & Heyi Zheng & Zhihong Wu & Yunping Zhu & Ling Leng, 2022. "Spatially resolved proteomic map shows that extracellular matrix regulates epidermal growth," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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