XL765 targets tumor growth, survival, and angiogenesis in preclinical models by dual inhibition of PI3K and mTOR

B250 The PI3K pathway is frequently dysregulated in cancer cells and is implicated in multiple aspects of tumor pathobiology, including tumor growth, survival, angiogenesis, and dissemination. In particular, activating mutations in PIK3CA, the gene encoding the catalytic subunit of PI3K (p110α), and/or loss of function/deletion mutations in the gene encoding its antagonist, the PTEN tumor suppressor, have been found in high frequencies over a wide range of tumor types. In addition, resistance to many anticancer agents (including receptor tyrosine kinase inhibitors and genotoxic agents) has been attributed to failure to downregulate PI3K pathway signaling. Current inhibitors of this signaling pathway include rapamycin and related molecules, which specifically inhibit the mTOR/Raptor complex. However, inhibition of mTOR/Raptor can lead to upregulation of PI3K activity, reflecting alleviation of an mTOR/Raptor-dependent negative feedback loop, with consequent activation of AKT-dependent survival pathways.
 XL765 is a potent, orally bioavailable inhibitor of both PI3K and mTOR. XL765 inhibits all four Class I PI3K isoforms and mTOR with IC50 values in the nanomolar range in biochemical assays, yet is highly selective against a panel of over 130 other human kinases. XL765 inhibits PI3K-dependent production of the second messenger PIP3, and nutrient-stimulated mTOR-dependent signaling in cellular assays. Moreover, XL765 inhibits PI3K- and/or mTOR-dependent phosphorylation of key PI3K pathway components including AKT, the AKT substrates PRAS40 and GSK3β, p70S6K, the p70S6K substrate S6, and 4E-BP1 in diverse cancer cells. Oral administration of XL765 to mice bearing xenografts of MCF-7 breast adenocarcinoma cells (positive for an activating mutation in PIK3CA) or PC-3 prostate adenocarcinoma cells (PTEN-deficient) resulted in significant inhibition of PI3K and mTOR signaling. XL765 significantly slowed tumor growth or caused tumor shrinkage in multiple xenograft tumor models, including breast, lung, ovarian, prostate, and brain cancers. These effects were correlated with inhibition of tumor cell proliferation and tumor angiogenesis, and with induction of apoptosis. In contrast, rapamycin inhibited proliferation but caused little or no induction of apoptosis. Consistent with these differences, substantial regression of tumors treated with XL765 but not with rapamycin was observed after cessation of dosing in a NSCLC xenograft model. These data suggest that a dual inhibitor strategy, targeting both PI3K and mTOR, may offer significant advantages over specifically targeting the mTOR/Raptor complex. XL765 is currently being administered to patients with solid tumors in a Phase I clinical trial.