title: mTOR is a selective effector of the radiation therapy response in androgen receptor-positive prostate cancer.
abstract: Ionizing radiation (IR) is used frequently in the management of multiple tumor types, including both organ-confined and locally advanced prostate cancer (PCa). Enhancing tumor radiosensitivity could both reduce the amount of radiation required for definitive treatment and improve clinical outcome. Androgen suppression therapy improves clinical outcomes when combined with radiation therapy but is associated with significant acute and chronic toxicities; hence, there is a clear need for alternative means to increase the therapeutic window of radiotherapy. Herein, it is demonstrated that the mammalian target of rapamycin (mTOR) inhibitors rapamycin (sirolimus) and temsirolimus limit both hormone therapy (HT)-sensitive and castration-resistant PCa (CRPC) cell proliferation as single agents and have a profound radiosensitization effect when used in combination with IR. Importantly, the observed radiosensitization was influenced by the treatment schedule, in which adjuvant administration of mTOR inhibitors was most effective in limiting PCa cell population doubling. This schedule-dependent influence on in vitro treatment outcome was determined to be the result of relative effects on the cell cycle kinetics. Finally, adjuvant administration of either mTOR inhibitor tested after IR significantly decreased clonogenic cell survival of both HT-sensitive and CRPC cells compared with IR alone. Taken together, these data demonstrate that inhibition of mTOR confers a radiosensitization phenotype that is dependent on relative cell cycle kinetics and provide a foundation for clinical assessment.
authors: Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors: Matthew J
authors: MJ
authors: Schiewer
authors: Robert
authors: R
authors: Den
authors: David T
authors: DT
authors: Hoang
authors: Michael A
authors: MA
authors: Augello
authors: Yaacov R
authors: YR
authors: Lawrence
authors: Adam P
authors: AP
authors: Dicker
authors: Karen E
authors: KE
authors: Knudsen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002470:Cell Survival; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D011944:Receptors, Androgen / Q000378:metabolism; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014965:X-Rays
chemical_list: D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; D011944:Receptors, Androgen; C401859:temsirolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus