Abstract B157: Selective class I PI3K inhibitor CH5132799 induces significant tumor regression with suppressing 4E-BP1 phosphorylation.

Abstract

Abstract The phosphatidylinositol 3-kinase (PI3K) pathway plays a central role in cell proliferation and survival in human cancer. Mutations of the PIK3CA gene, which encodes the class I PI3K catalytic subunit p110, are found in many cancer patients and activate the PI3K pathway, resulting in cancer development and progression. We previously identified CH5132799 as a novel inhibitor, selective to class I PI3K and with potent antitumor activity against tumors harboring PIK3CA mutations. Here we investigated the relationship between in vivo efficacy and PI3K signaling inhibition. CH5132799 suppressed tumor growth in a wide variety of xenograft models with PI3K pathway activation, including those with PIK3CA mutations. CH5132799 has two modes of tumor growth inhibition, tumor regression and tumor stasis. On the one hand, in the breast cancer xenograft models harboring PIK3CA mutations (KPL-4 and BT-474), CH5132799 induced remarkable tumor regression and also shrank the tumor of PTEN-deleted prostate cancer GXF-97 (‘tumor regression models’). On the other hand, in colorectal cancers with both PIK3CA and KRAS mutations (HCT116 and HCT15), CH5132799 treatment resulted in tumor stasis but did not induce tumor regression (‘tumor stasis models’). We analyzed PI3K and MAPK signaling in these xenograft tumors to explore the factors which could explain the tumor growth inhibition modes of CH5132799, tumor regression or stasis. Phosphorylation of Akt and S6 was inhibited by CH5132799 administration in all the tested tumors but ERK phosphorylation was not. Notably, 4E-BP1 phosphorylation (p-4E-BP1) was well suppressed in the tumor regression models but was only partially decreased in the tumor stasis models. These findings suggest that p-4E-BP1 determines whether CH5132799 induces tumor regression or stasis. Since p-4E-BP1 is known to be regulated by both PI3K and MAPK pathways, we examined the effects on p-4E-BP1 of combining inhibitors selective to each pathway: CH5132799 and RO4987655, an allosteric MEK inhibitor. Compared to their effect as single agents, the combined inhibitors drastically suppressed p-4E-BP1 in HCT116 cells in vitro, leading to potent growth inhibition and apoptosis induction. Furthermore, combining CH5132799 and RO4987655 induced remarkable in vivo tumor regression even in the HCT116 tumor stasis model, confirming the significance of p-4E-BP1 suppression in CH5132799-induced tumor regression. In conclusion, tumor regression or stasis induced by CH5132799 correlated with p-4E-BP1 being suppressed in the tumors. Moreover, in the model in which CH5132799 alone had induced tumor stasis with partial p-4E-BP1 suppression, combination with the MEK inhibitor achieved p-4E-BP1 suppression and tumor regression. From these lines of preclinical evidence, p-4E-BP1 suppression could also be a determinant factor of the CH5132799 response in clinical settings, and combination therapy with MEK inhibitors is a promising strategy to enhance CH5132799 efficacy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B157.