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Protein kinase C-θ regulates KIT expression and proliferation in gastrointestinal stromal tumors

Oncogene volume 27, pages 5624–5634 (2008)Cite this article

Abstract

Oncogenic KIT or PDGFRA receptor tyrosine kinase mutations are compelling therapeutic targets in gastrointestinal stromal tumors (GISTs), and the KIT/PDGFRA kinase inhibitor, imatinib, is standard of care for patients with metastatic GIST. However, most of these patients eventually develop clinical resistance to imatinib and other KIT/PDGFRA kinase inhibitors and there is an urgent need to identify novel therapeutic strategies. We reported previously that protein kinase C-θ (PKCθ) is activated in GIST, irrespective of KIT or PDGFRA mutational status, and is expressed at levels unprecedented in other mesenchymal tumors, therefore serving as a diagnostic marker of GIST. Herein, we characterize biological functions of PKCθ in imatinib-sensitive and imatinib-resistant GISTs, showing that lentivirus-mediated PKCθ knockdown is accompanied by inhibition of KIT expression in three KIT+/PKCθ+ GIST cell lines, but not in a comparator KIT+/PKCθ− Ewing's sarcoma cell line. PKCθ knockdown in the KIT+ GISTs was associated with inhibition of the phosphatidylinositol-3-kinase/AKT signaling pathway, upregulation of the cyclin-dependent kinase inhibitors p21 and p27, antiproliferative effects due to G1 arrest and induction of apoptosis, comparable to the effects seen after direct knockdown of KIT expression by KIT short-hairpin RNA. These novel findings highlight that PKCθ warrants clinical evaluation as a potential therapeutic target in GISTs, including those cases containing mutations that confer resistance to KIT/PDGFRA kinase inhibitors.

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Acknowledgements

This work was supported by grants from an anonymous donor, GI SPORE 1P50CA127003-01, the Life Raft Group, Cesarini Team for the Pan-Massachusetts Challenge, the Virginia and Daniel K Ludwig Trust for Cancer Research, the Ronald O Perelman Fund for Cancer Research, the Stutman GIST Cancer Research Fund, the Rubenstein Foundation and Leslie's Links. We thank Sarah E Bulmer and William Hahn for providing shRNA constructs.

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Authors and Affiliations

  1. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA

    W-b Ou, M-j Zhu, C D M Fletcher & J A Fletcher

  2. Ludwig Center, Dana-Farber/Harvard Cancer Center, Boston, MA, USA

    G D Demetri

  3. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    G D Demetri

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  1. W-b Ou
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  2. M-j Zhu
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Correspondence to W-b Ou or J A Fletcher.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Ou, Wb., Zhu, Mj., Demetri, G. et al. Protein kinase C-θ regulates KIT expression and proliferation in gastrointestinal stromal tumors. Oncogene 27, 5624–5634 (2008). https://doi.org/10.1038/onc.2008.177

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