Reciprocal feedback inhibition of the androgen receptor and PI3K as a novel therapy for castrate-sensitive and -resistant prostate cancer.
Gain-of-function of the androgen receptor (AR) and activation of PI3K/AKT/mTOR pathway have been demonstrated to correlate with progression to castration-resistant prostate cancer (CRPC). However, inhibition of AR or PI3K/mTOR alone results in a reciprocal feedback activation. Therefore, we hypothesized that dual inhibition of the AR and PI3K/mTOR pathway might lead to a synergistic inhibition of cell growth and overcome drug resistance in CRPC. Here, we reported that androgen-depletion increased AR protein level and Akt phosphorylation at Ser473 and Thr308 in LNCaP cells. Moreover, we developed resistance cell lines of LNCaP to Enzalutamide (or MDV3100), an AR inhibitor (named as LNCaP 'MDV-R') and PF-04691502, a PI3K/mTOR inhibitor (named as LNCaP 'PF-R'). MTS analysis showed that LNCaP 'PF-R' was strongly resistant to Enzalutamide treatment, and on the other hand, LNCaP 'MDV-R' was 6-fold resistant to PF-04691502 treatment. Mechanistically, LNCaP 'MDV-R' cells had significantly reduced AR, loss of PSA and increase Akt activity in contrast with LNCaP 'PF-R' cells. Combined inhibition of PI3K/mTOR and AR pathways with a variety of small molecular inhibitors led to a synergistic suppression of cell proliferation and a profound increase of apoptosis and cell cycle arrest in both androgen-dependent LNCaP and independent CRPC 22Rv1 cell lines. In conclusion, this study provides preclinical proof-of-concept that the combination of a PI3K/mTOR inhibitor with an AR inhibitor results in a synergistic anti-tumor response in non-CRPC and CRPC models.
West Cancer Center/University of Tennessee Health Science Center (UTHSC), Memphis, TN, USA.
Wenqing
W
Qi
West Cancer Center/University of Tennessee Health Science Center (UTHSC), Memphis, TN, USA.
Carla
C
Morales
West Cancer Center/University of Tennessee Health Science Center (UTHSC), Memphis, TN, USA.
Laurence S
LS
Cooke
West Cancer Center/University of Tennessee Health Science Center (UTHSC), Memphis, TN, USA.
Benny
B
Johnson
West Cancer Center/University of Tennessee Health Science Center (UTHSC), Memphis, TN, USA.
Bradley
B
Somer
West Cancer Center/University of Tennessee Health Science Center (UTHSC), Memphis, TN, USA.
Daruka
D
Mahadevan
D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D025461:Feedback, Physiological / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D008297:Male; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D064129:Prostatic Neoplasms, Castration-Resistant / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D009570:Nitriles; D010669:Phenylthiohydantoin; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011728:Pyridones; D011743:Pyrimidines; D011944:Receptors, Androgen; D058570:TOR Serine-Threonine Kinases; C569670:1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno(3,2-d)pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one; C570662:2-amino-8-(4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido(2,3-d)pyrimidin-7(8H)-one; C540278:enzalutamide; C546842:MTOR protein, human
AR and PI3K/mTOR inhibitors resistant LNCaP cells; PI3K/AKT/mTOR; androgen receptor; hormone sensitive and resistant prostate cancer