Dual inhibition of PI3K and mTOR inhibits autocrine and paracrine proliferative loops in PI3K/Akt/mTOR-addicted lymphomas.

Authors:
Sang-Hoon Sin
Sang-Hoon Sin
Dept. Microbiology & Immunology / University of North Carolina at Chapel Hill
Research Assistant Professor
KSHV
Chapel Hill, NC | United States

Blood 2010 Jun 18;115(22):4455-63. Epub 2010 Mar 18.

Lineberger Comprehensive Cancer Center and Department of Microbiology & Immunology, University of North Carolina at Chapel Hill, NC 27599, USA.

Primary effusion lymphoma (PEL) constitutes a subset of non-Hodgkin lymphoma whose incidence is highly increased in the context of HIV infection. Kaposi sarcoma-associated herpesvirus is the causative agent of PEL. The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays a critical role in cell proliferation and survival, and this pathway is dysregulated in many different cancers, including PEL, which display activated PI3K, Akt, and mammalian target of rapamycin (mTOR) kinases. PELs rely heavily on PI3K/Akt/mTOR signaling, are dependent on autocrine and paracrine growth factors, and also have a poor prognosis with reported median survival times of less than 6 months. We compared different compounds that inhibit the PI3K/Akt/mTOR pathway in PEL. Although compounds that modulated activity of only a single pathway member inhibited PEL proliferation, the use of a novel compound, NVP-BEZ235, that dually inhibits both PI3K and mTOR kinases was significantly more efficacious in culture and in a PEL xenograft tumor model. NVP-BEZ235 was effective at low nanomolar concentrations and has oral bioavailability. We also report a novel mechanism for NVP-BEZ235 involving the suppression of multiple autocrine and paracrine growth factors required for lymphoma survival. Our data have broad applicability for the treatment of cytokine-dependent tumors with PI3K/mTOR dual inhibitors.

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Source
http://dx.doi.org/10.1182/blood-2009-10-251082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881502PMC
June 2010
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