1. ¹Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
2. ²Ludwig Center, Dana-Farber/Harvard Cancer Center, Boston, MA, USA
3. ³Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

Correspondence: Dr W Ou, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA. E-mail: wou@rics.bwh.harvard.edu; JA Fletcher, E-mail: jfletcher@partners.org

Received 2 January 2008; Revised 10 April 2008; Accepted 28 April 2008; Published online 2 June 2008.

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- (PKC) 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 PKC in imatinib-sensitive and imatinib-resistant GISTs, showing that lentivirus-mediated PKC knockdown is accompanied by inhibition of KIT expression in three KIT+/PKC+ GIST cell lines, but not in a comparator KIT+/PKC- Ewing's sarcoma cell line. PKC 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 PKC warrants clinical evaluation as a potential therapeutic target in GISTs, including those cases containing mutations that confer resistance to KIT/PDGFRA kinase inhibitors.