Abstract A23: Differentiation of PI3K/Akt/mTOR inhibition in cancer models using dual dissociative TORC1/TORC2 (P529), single dissociative TORC1 (rapalogs) and catalytic inhibitors (PI3K/Akt, PI3K/mTOR)

P529 is a first-in-class, allosteric, small molecule, dual dissociative inhibitor of the TORC1 and TORC2 protein complexes within the PI3K/Akt/mTOR pathway. P529 has been previously shown to cause the rapid dissociation of the TORC1 and TORC2 complexes both in vitro and in vivo tumor xenograft models. Other PI3K inhibitors include rapalogs which cause the dissociation of the TORC1 complex and, PI3K/mTOR and PI3K/Akt inhibitors aimed at protein kinase catalytic site inhibition. Although these inhibitors have shown some utility in inhibiting cancer growth, they have deficiencies inherent to their mechanism of action. Rapalogs have been shown to stimulate the PI3K pathway through the induction of the IRS-1 negative feedback loop. Although mTOR resides in both TORC1 and TORC2, catalytic inhibition of mTOR does not dissociate both complexes allowing other proteins within the complexes to retain and exert signalling activity. Hence they are not true dual TORC1/TORC2 inhibitors, but only mTOR inhibitors. Here we show comparison of P529 with rapalogs and the catalytic inhibitors PI3K/mTOR and PI3K/Akt delineating activity in prostate, lung, glioblastoma and hepatic tumor evaluating cell survival, phosphoprotein PI3K signaling (IC50), CT scanning, tumor volume and growth arrest in cellular models and murine xenografts, showing superiority of allosteric dual TORC1/TORC2 dissociative inhibition. Furthermore, in addition to evaluation in cancer treatment models, data will be presented showing activity in cancer prevention using the mutant EGFR (L858R/T790M) transgene lung expression model. Citation Format: David Sherris, Philip A. Dennis, Willie Wilson, III, Shigeru Kawabata, Chunrong Yu, Giovanni Luca Gravina, Andrea Mancini, Claudio Festuccia. Differentiation of PI3K/Akt/mTOR inhibition in cancer models using dual dissociative TORC1/TORC2 (P529), single dissociative TORC1 (rapalogs) and catalytic inhibitors (PI3K/Akt, PI3K/mTOR). [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr A23.