Abstract 1798: TORC1/2 inhibitors have more potent anti-leukemic efficacy and are less immunosuppressive than rapamycin

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC The purpose of this study was to evaluate the anti-leukemic and immunosuppressive properties of novel, ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR). The mTOR inhibitors currently in clinical use, exemplified by rapamycin and related analogs (“rapalogs”), have achieved some success as anticancer therapies. However, these agents also suppress proliferation of both B and T lymphocytes. In addition, rapalogs have a mechanistic limitation: not only are they allosteric inhibitors that selectively bind to mTOR complex-1 (TORC1) and not to mTOR complex-2 (TORC2), but they do not fully inhibit TORC1. In contrast, novel ATP-competitive active-site inhibitors of the mTOR kinase overcome these limitations, displaying full inhibitory activity of both TORC1 and TORC2. We compared rapamycin with active-site TORC1/2 inhibitors in models of Philadelphia chromosome-positive pre-B acute lymphoblastic leukemia (Ph+ B-ALL). We find that PP242 and INK128, active-site TORC1/2 inhibitors, but not rapamycin cause death of murine and primary human leukemia cells. These compounds are also more potent than rapamycin in growth assays of solid tumor cell lines. Biochemical assays confirm that PP242 and INK128 inhibit rapamycin-resistant outputs of both TORC1 and TORC2. In vivo, oral administration of PP242 or INK128 delays leukemia onset and augments the effects of tyrosine kinase inhibitors. Surprisingly, active-site TORC1/2 inhibitors have much weaker effects on proliferation and function of normal B and T cells than rapamycin. Selective TORC1/2 inhibitors are also less immunosuppressive than PI-103, a panPI3K-mTORC1/2 inhibitor. These findings establish that transformed lymphocytes are selectively sensitive to TORC1/2 inhibitors and support the development of such inhibitors for leukemia therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1798.