Abstract C65: Enhanced antitumor effect by the combination of a PI3K inhibitor ZSTK474 with an mTOR inhibitor rapamycin

• Published in: Molecular cancer therapeutics Vol. 8; no. 12_Supplement; p. C65
• Main Authors: Yoshimi, Hisashi, Okamura, Mutumi, Yamazaki, Kanami, Yamori, Takao
• Format: Journal Article
• Language: English
• Published: 10.12.2009
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.TARG-09-C65

Abstract PI3K is a promising molecular target for the therapy of cancer. Various PI3K inhibitors are now under development. We developed a novel PI3K inhibitor ZSTK474 and demonstrated its potent antitumor efficacy. ZSTK474 is highly specific to PI3K and does not inhibit other kinases including mTOR that is a down stream component of PI3K pathway. The purpose of this study was to examine whether dual inhibition of PI3K and mTOR further improved antitumor efficacy. To assess the effect of the combination of ZSTK474 and rapamycin on prostate cancer PC-3 cells and lung cancer A549 cells in vitro, we used the isobologram method. The combination of ZSTK474 and rapamycin showed a supra-additive effect (synergism) on both PC-3 and A549. We then evaluated the efficacy of the combination of ZSTK474 with an mTOR inhibitor rapamycin against the xenografts of PC-3 and A549. Suboptimal doses of ZSTK474 and rapamycin were determined as 100 mg/kg/day (p.o., from day 0 to day 14, except days 3 and 10) and 0.1 mg/kg/day (i.p., from day 0 to day 5 except day 3), respectively. Then, the combination of the two drugs was compared to the single drug treatments. The combination of ZSTK474 and rapamycin showed almost complete inhibition of the tumor growth whereas each single drug treatment showed partial inhibition. The synergy in the toxicity was not observed. We examined the effects of the combination on the PI3K/Akt downstream molecules in the PC-3 tumor tissues by immunohistochemical technique. The single treatment of ZSTK474 reduced the phosphorylation of Akt (Ser473), GSK3-beta and 4E-BP1, and partially reduced the phosphorylation of S6 and the expression of Cyclin D1. The single treatment of rapamycin reduced the phosphorylation of 4E-BP1, and partially reduced the phosphorylation of S6 and the expression of Cyclin D1, but did not reduce the phosphorylation of Akt (Ser473) or that of GSK3-beta. The combination of ZSTK474 and rapamycin reduced the phosphorylation of Akt, GSK3-beta, 4E-BP1 and S6, and the expression of Cyclin D1. These results confirmed the therapeutic efficacy of the combination of ZSTK474 and rapamycin against PC-3 xenografts. Therefore, the combination of PI3K inhibitor and mTOR inhibitor may be effective for cancer therapy. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C65.