Enzastaurin (LY317615.HCl) inhibits human lung cancer cells in vitro and in vivo: a pharmacodynamic study

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 5407 PKCβ is a member of the PKC family of serine-threonine protein kinases which have been implicated in human cancer proliferation, cell cycle progression, angiogenesis and apoptosis. Enzastaurin (LY317615), a selective PKCβ inhibitor, has been shown to inhibit a variety of human tumors including glioblastoma, colon, prostate and lung cancer cell lines in vitro. Elevated phosphorylation and altered PKC expression has been demonstrated in several NSCLC cell lines versus normal lung epithelia cell lines. In this presentation we show that enzastaurin inhibited the growth of 14 NSCLC cell lines with average IC50 of 8.2 µM, ranging 1.5 to 20 µM and 14 SCLC cell lines with average IC50 of 7.0 µM, ranging 3 to 10 µM. The sensitivities toward enzastaurin among the four different NSCLC histologies (adenocarcinomas, squamous, large cell carcinomas or bronchial alveolar carcinoma) are very similar. By western blot analysis, we found that enzastaurin significantly reduced phosphorylation of GSK3β (Ser9), ribosomal protein S6 (Ser240 /244) but not in phospho-AKT(Thr308) in both NSCLC and SCLC cell lines. Using Combination-Index analysis, when enzastaurin was combined with pemetrexed concurrently or pemetrexed followed by enzastaurin sequentially, the interaction is greater than additive. Our in vivo studies showed that enzastaurin by daily BID oral gavages at 38, 75 and 150 mg/kg suppressed human lung xenografts H2122 adenocarcinomas in athymic nude mice, but not in a dose-dependent manner. In conjunction with efficacious studies of enzastaurin in tumor bearing nude mice, plasma pharmacokinetics were evaluated on day 3, 10 or 21 following the start of dosing. The plasma enzastaurin levels for these days were found to be 1180±58.6, 931.3±399 and 1018.7±158 ng/ml for 38 mg/kg dose; 636.5±414, 2093.3±432 and 1830±355 ng/ml for 75 mg/kg dose; 2473.3±169, 2906.7±370 and 5020±790 ng/ml for 150 mg/kg respectively, supporting the observed therapeutic effects of enzastaurin against human lung xenografts. Our preclinical data provided strong evidence that enzastaurin may be effective for the treatment of human lung cancers.