Abstract A172: INK128, an orally active TORC1/2 kinase inhibitor, displays enhanced efficacy when combined with cytotoxic agents.

Abstract

Abstract Background: The mammalian target of rapamycin (mTOR) comprises two protein complexes, TORC1 and TORC2, which together regulate cell growth, metabolism, angiogenesis, and cell survival. Because TORC1 and TORC2 play a crucial role in several pathways that are frequently dysregulated in human cancer, the TORC1/2 kinase inhibitors provide a promising class of anti-cancer agents. Activation of multiple genomic and signaling pathways, cross-feedback, pathway redundancy and the capacity for compensatory adaptive response in cancer suggest that the optimal therapeutic effect of mTOR inhibitors will be better exploited by the strategy of rational combination therapies. Results: INK128 is a potent and selective TORC1/2 inhibitor with excellent drug-like properties currently in multiple phase 1 studies. Daily, oral administration of INK128 inhibits tumor growth in multiple xenograft models with predicted pharmacokinetic/pharmacodynamic relationship. In most instances the anti-tumor effect of INK128 is cytostatic compared to the cytotoxic effect of chemotherapeutic agents such as Taxol. To enhance the anti-tumor activity of INK128, we investigated the combination of INK128 with cytotoxic agents such as conventional chemo drugs or apoptosis inducing agents. Treatment of tumors with the cytotoxic agents such as Taxol often leads to activation of the PI3K/AKT/mTOR pathway, which limits the anti-tumor activity of Taxol and may eventually lead to drug resistance. Additionally, Taxol resistance mechanisms include the over-expression of members of the Bcl-2 family of proteins such as MCL-1 and BCL-XL, whose expression is regulated by TORC1 and their function possibly by TORC2. Therefore, there is a strong scientific rationale to investigate the combination of a TORC1/2 inhibitor and Taxol. To this end, we have investigated the preclinical efficacy of INK128 in combination with Taxol in vitro and in vivo. Combining INK128 with Taxol resulted in a synergistic inhibition of tumor cell proliferation and the suppression of PI3K/AKT/mTOR signaling pathways in various cancer types. In most instances alterations in cell cycle and an increase in apoptosis was observed. INK128 decreases the expression of anti-apoptotic protein Mcl-1 and therefore resensitizes Taxol-resistant tumor cells to Mcl-1-dependent build up. In various xenograft models, the combination therapies were well-tolerated and displayed enhanced anti-tumor efficacy, inhibited pharmacodynamic markers, and induced apoptosis. Combination of INK128 with a small molecule inhibitor of Bcl-2 (ABT-263) also led to significant increase of apoptosis in tumor cells but not in normal cells in vitro and enhanced anti-tumor activity in mouse tumor models in vivo. Conclusion: In summary, our data show a potential benefit for combining INK128 with cytotoxic agents. INK128 is currently in a Taxol combination phase Ib study in patients with advanced solid malignancies. 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 A172.