Abstract A50: Targeting 3-phosphoinositide-dependent kinase-1 and mammalian target of rapamycin synergistically inhibits cell proliferation of breast cancer cells

Aberration of receptor tyrosine kinases (RTKs), PTEN (phosphatase and tensin homolog deleted on chromosome 10), and PIK3CA (encodes the p110 subunit of phosphatidylinositol 3-kinase [PI3K]) frequently contribute to tumor progression through their ability to regulate the intracellular level of phosphatidylinositol-3,4,5- triphosphate (PIP₃). PIP₃ subsequently recruits 3-phosphoinositide- dependent kinase-1 (PDK-1), a serine/threonine kinase, to the plasma membrane and initiates PDK-1 kinase activity to phosphorylate AKT within the activation loop of the catalytic domain at the residue threonine-308 (T308). The mammalian target of rapamycin (mTOR) plays a critical role in the PI3K/AKT pathway. The mTOR kinase is present as two protein complexes, TORC1 and TORC2. The TORC1 complex is activated by PI3K/AKT and phosphorylates p70S6K and 4E-BP1 to modulate protein translation whereas the TORC2 complex phosphorylates AKT in the regulatory domain at residue serine 473 (S473). Phosphorylation of AKT at both T308 and S473 fully activates AKT function through downstream signaling to mediate cell proliferation, survival, migration, angiogenesis and other pathways which are critical for tumor progression. We have developed a potent and selective PDK1 inhibitor (PF-05177624) that is sufficient to inhibit the phosphorylation of AKT atT308 and block cell proliferation of cancer cells in vitro. In this study, we combined this PDK1 inhibitor (PF-05177624) and a selective mTOR kinase inhibitor (WYE-354) to perform the combination studies in breast cancer cell lines. Our data demonstrate that targeting both PDK1 and mTOR simultaneously produces a synergistic inhibitory effect in AKT phosphorylation. Moreover, this results in a synergistic inhibition of cell proliferation in breast cancer cells. Our data suggest that a combination strategy of targeting both PDK-1 and mTOR may have potential improved clinical efficacy in the development of cancer drugs for breast cancer patients.

Citation Information: Clin Cancer Res 2010;16(14 Suppl):A50.