Protein kinase C-theta 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-theta (PKCtheta) 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 PKCtheta in imatinib-sensitive and imatinib-resistant GISTs, showing that lentivirus-mediated PKCtheta knockdown is accompanied by inhibition of KIT expression in three KIT+/PKCtheta+ GIST cell lines, but not in a comparator KIT+/PKCtheta- Ewing's sarcoma cell line. PKCtheta 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 PKCtheta warrants clinical evaluation as a potential therapeutic target in GISTs, including those cases containing mutations that confer resistance to KIT/PDGFRA kinase inhibitors.
Ou
W-b
WB
1Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. wou@rics.bwh.harvard.edu
Zhu
M-j
MJ
Demetri
G D
GD
Fletcher
C D M
CD
Fletcher
J A
JA
D017209:Apoptosis; D001483:Base Sequence; D001549:Benzamides; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D046152:Gastrointestinal Stromal Tumors / Q000473:pathology*; D006801:Humans; D000068877:Imatinib Mesylate; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology*; D008969:Molecular Sequence Data; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000235:genetics / Q000502:physiology*; D000074121:Protein Kinase C-theta; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction
D001549:Benzamides; D007527:Isoenzymes; D010879:Piperazines; D011743:Pyrimidines; D034741:RNA, Small Interfering; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta