Combining an mTOR antagonist and receptor tyrosine kinase inhibitors for the treatment of prostate cancer.
Inhibition of the mammalian target of rapamycin (mTOR) signaling pathway is a potentially useful therapeutic strategy in the treatment of advanced prostate cancer. However mTOR antagonists used as single agents are not likely to result in dramatic clinical responses, so that it is useful to identify prospective agents that might be useful in combination. We treated CWR22Rv1 and LNCaP prostate cancer cells with an mTOR inhibitor, rapamycin, alone, or in combination with either of two receptor protein kinase (RTK) inhibitors. We assessed the effects of these treatments on cell survival and activation of down-stream mTOR target proteins. Treatment with either PD16839, an EGFr antagonist, or imatinib mesylate (Gleevec), a PDGFr, c-kit and bcr/abl antagonist, enhanced the anti-proliferative effects of rapamycin. We therefore assessed the effects of treatment with the RTK antagonist alone and in combination with rapamycin on mTOR targeted proteins. RTK antagonists alone had no effect or paradoxically increased phosphorylation of the mTOR targeted proteins, p70 S6 kinase and ribosomal S6. In contrast, when these cells were treated with either RTK antagonist in the presence of rapamycin, there was a dramatic decrease in phosphorylation of these two mTOR-targeted proteins. These effects were not mediated through phospho-AKT. Since two separate RTK antagonists had additive antiproliferative effects in combination with an mTOR antagonist and were associated with a dramatic decrease in mTOR targeted proteins in cells with or without PTEN expression, the strategy deserves further evaluation for the treatment of prostate cancer.
Masiello
David
D
Cancer Biology Program, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, 300 Brookline Avenue, Boston, MA 02215, USA.
Mohi
M Golam
MG
McKnight
Nicole C
NC
Smith
Bradley
B
Neel
Ben G
BG
Balk
Steven P
SP
Bubley
Glenn J
GJ
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases; D011743:Pyrimidines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011494:Protein Kinases; C546842:MTOR protein, human; D020794:Receptor Protein-Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus