Abstract 2224: Targeted PI3K/mTOR inhibition impairs tumor cell motility and bone metastatic outgrowth via modulation of p27

The pleiotropic oncogenic effects of PI3K/mTOR have stimulated development of catalytic PI3K and mTOR inhibitors for the treatment of cancer. Present data provide a novel rationale for the use of dual PI3K/mTOR inhibitors to oppose tumor motility, invasion and metastasis. Cytoplasmic mislocalization of p27 is implicated as a key downstream driver of PI3K/mTOR-dependent tumor cell motility in vitro and bone metastatic outgrowth in vivo. Here, we report that PI3K/mTOR-kinase inhibition with PF-04691502 impairs breast cancer metastasis to bone, in part via effects on p27. Low-dose PF-04691502 impaired motility and invasion of highly PI3K/mTOR activated, bone-metastatic MDA-MB-1833 cells in vitro without affecting apoptosis or proliferation. Moreover, drug pre-treatment impaired bone metastasis in vivo. PF-04691502 decreased cytoplasmic p27pT157 and p27pT198, and p27T157D/T198D overexpression conferred resistance to inhibition of motility by PF-04691502. p27 knockdown in MDA-MB-1833 relieved RhoA-ROCK inhibition, decreased cell motility/invasion in vitro, and bone metastasis in vivo. p27 knockdown also reversed EMT phenotypic markers in MDA-MB-1833, as did PI3K/mTOR inhibition, demonstrating that p27 may be critical for maintenance of the EMT cellular program. Indeed, loss of cytoplasmic p27 reversed expression of an EMT gene profile supporting the notion that p27 acts as a key mediator of metastasis downstream of PI3K/mTOR. Cytoplasmic p27 in human cancers may prove to be a useful predictive marker to assess both PI3K/mTOR activation and the potential efficacy of catalytic PI3K/mTOR inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2224. doi:1538-7445.AM2012-2224