Abstract 2160: MEN1611, a novel α-selective PI3K inhibitor in solid tumors

The PI3K pathway regulates various cellular processes such as proliferation, growth, apoptosis and cytoskeletal rearrangement. This pathway is frequently de-regulated and considered an oncogenic driver in human cancer. In most solid tumors, the activation of the PI3K pathway is induced by mutations of the catalytic subunit PI3Kα, present in approximately 20% to 50% of breast cancer, 14% of colorectal cancer and in 5-10% of NSCLC. Besides being an actionable target, the PI3K pathway is implicated in de novo and acquired treatment resistant in various tumor types treated with targeted therapy. As a matter of fact, the most interesting antitumor activity with PI3K inhibitors has been observed in combination. Here, we present MEN1611 (previously PA799), a PI3-kinase inhibitor with a peculiar biochemical profile targeting with high inhibition potency the mutated forms of PI3Kα and PI3Kγ. In the current study we demonstrate the anticancer activity and the pharmacodynamic effects of MEN1611 as monotherapy or in combination with targeted therapies in both xenograft and PDX models of breast cancer and in colorectal cancer and in NSCLC models, all with defined genetic profiles. MEN1611, at a clinically relevant dose, showed good antitumor activity in combination with targeted therapy agents against breast cancer, colorectal cancer and NSCLC models bearing PI3Kα mutations. A reduced activity was instead observed when the tumor models were wild type for PI3Kα or had low levels of PTEN. The antitumor activity of MEN611 was supported by its pharmacodynamic activity. In all the models, both AKT and S6 phosphorylation, markers of PI3K inhibition, were significantly inhibited upon treatment. In agreement with the biochemical profile of the drug, in PTEN null xenograft models where the tumor driver is the PI3K β-isoform, we observed lower effects in term of antitumor activity and of molecular inhibition of the pathway. Last, MEN1611 induction of hyperglycemia and insulin release was studied in the tumor models at clinical relevant dose as a marker of class-effect toxicity. MEN1611 showed significant antitumor activity in combination with other targeted therapies in breast, colon and NSCL cancer PI3Kα mutant models. Our results support the evidence that MEN611 is a PI3Kα specific inhibitor and provided the basis for the planned phase IB/II. Citation Format: Giuseppe Merlino, Alessio Fiascarelli, Mario Bigioni, Alessandro Bressan, Clelia Irrissuto, Andrea Pellacani, Maurizio Scaltriti, Monica Binaschi. MEN1611, a novel α-selective PI3K inhibitor in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2160.