title: Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model.
abstract: The AKT/mammalian target of rapamycin (AKT/mTOR) and ERK MAPK signaling pathways have been shown to cooperate in prostate cancer progression and the transition to androgen-independent disease. We have now tested the effects of combinatorial inhibition of these pathways on prostate tumorigenicity by performing preclinical studies using a genetically engineered mouse model of prostate cancer. We report here that combination therapy using rapamycin, an inhibitor of mTOR, and PD0325901, an inhibitor of MAPK kinase 1 (MEK; the kinase directly upstream of ERK), inhibited cell growth in cultured prostate cancer cell lines and tumor growth particularly for androgen-independent prostate tumors in the mouse model. We further showed that such inhibition leads to inhibition of proliferation and upregulated expression of the apoptotic regulator Bcl-2-interacting mediator of cell death (Bim). Furthermore, analyses of human prostate cancer tissue microarrays demonstrated that AKT/mTOR and ERK MAPK signaling pathways are often coordinately deregulated during prostate cancer progression in humans. We therefore propose that combination therapy targeting AKT/mTOR and ERK MAPK signaling pathways may be an effective treatment for patients with advanced prostate cancer, in particular those with hormone-refractory disease.
authors: Department of Urology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
authors: Carolyn Waugh
authors: CW
authors: Kinkade
authors: Mireia
authors: M
authors: Castillo-Martin
authors: Anna
authors: A
authors: Puzio-Kuter
authors: Jun
authors: J
authors: Yan
authors: Thomas H
authors: TH
authors: Foster
authors: Hui
authors: H
authors: Gao
authors: Yvonne
authors: Y
authors: Sun
authors: Xuesong
authors: X
authors: Ouyang
authors: William L
authors: WL
authors: Gerald
authors: Carlos
authors: C
authors: Cordon-Cardo
authors: Cory
authors: C
authors: Abate-Shen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006728:Hormones / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008954:Models, Biological; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011494:Protein Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006728:Hormones; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases