Dual blockade of lipid and cyclin-dependent kinases induces synthetic lethality in malignant glioma

• Published in: Proceedings of the National Academy of Sciences - PNAS 2012-07, Vol.109 (31), p.12722-12727
• Main Authors: Cheng, Christine K., Gustafson, W. Clay, Charron, Elizabeth, Houseman, Benjamin T., Zunder, Eli, Goga, Andrei, Gray, Nathanael S., Pollok, Brian, Oakes, Scott A., James, C. David, Shokat, Kevan M., Weiss, William A., Fan, Qi-Wen
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis; Apoptosis - drug effects; Biological Sciences; Brain cancer; CDC2 Protein Kinase - antagonists & inhibitors; CDC2 Protein Kinase - metabolism; Cell death; Cell Line, Tumor; Cell lines; Cells; Cyclin-Dependent Kinase 2 - antagonists & inhibitors; Cyclin-Dependent Kinase 2 - metabolism; Cyclin-dependent kinases; Cytometry; Female; Glioma; Glioma - drug therapy; Glioma - enzymology; Heterologous transplantation; Humans; Lipids; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - metabolism; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; Protein Kinase Inhibitors - pharmacology; Purines - pharmacology; Small interfering RNA; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1202492109

Malignant glioma, the most common primary brain tumor, is generally incurable. Although phosphatidylinositol-3-kinase (PI3K) signaling features prominently in glioma, inhibitors generally block proliferation rather than induce apoptosis. Starting with an inhibitor of both lipid and protein kinases that induced prominent apoptosis and that failed early clinical development because of its broad target profile and overall toxicity, we identified protein kinase targets, the blockade of which showed selective synthetic lethality when combined with PI3K inhibitors. Prioritizing protein kinase targets for which there are clinical inhibitors, we demonstrate that cyclin-dependent kinase (CDK) 1/2 inhibitors, siRNAs against CDK1/2, and the clinical CDK1/2 inhibitor roscovitine all cooperated with the PI3K inhibitor PIK-90, blocking the antiapoptotic protein Survivin and driving cell death. In addition, overexpression of CDKs partially blocked some of the apoptosis caused by PIK-75. Roscovitine and PIK-90, in combination, were well tolerated in vivo and acted in a synthetic-lethal manner to induce apoptosis in human glioblastoma xenografts. We also tested clinical Akt and CDK inhibitors, demonstrating induction of apoptosis in vitro and providing a preclinical rationale to test this combination therapy in patients.