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

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 G 1 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.