Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model.
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.
Kinkade
Carolyn Waugh
CW
Department of Urology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Castillo-Martin
Mireia
M
Puzio-Kuter
Anna
A
Yan
Jun
J
Foster
Thomas H
TH
Gao
Hui
H
Sun
Yvonne
Y
Ouyang
Xuesong
X
Gerald
William L
WL
Cordon-Cardo
Carlos
C
Abate-Shen
Cory
C
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
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