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Current Cancer Drug Targets


ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Disrupting the mTOR Signaling Network as a Potential Strategy for the Enhancement of Cancer Radiotherapy

Author(s): Francis J. Dumont and Pierre Bischoff

Volume 12, Issue 8, 2012

Page: [899 - 924] Pages: 26

DOI: 10.2174/156800912803251243

Price: $65


Radiotherapy (RT) allows for tumor control through the cytotoxic action of ionizing radiation (IR). Although modern technologies permit precise IR delivery to the tumor mass while minimizing exposure of surrounding healthy tissues, the efficacy of RT remains limited by the intrinsic or acquired radioresistance of many tumors. There is thus an ongoing search for agents that augment the sensitivity of tumor cells to IR cytotoxicity, with recent interest in targeting components of signaling pathways involved in tumor growth and radioresistance. Here, we review the evidence suggesting that disabling one of these components, the mechanistic target of rapamycin (mTOR) kinase, may enhance RT efficacy. This molecule constitutes the catalytic subunit of the mTORC1 and mTORC2 protein complexes, which regulate cell growth and other processes implicated in tumorigenesis. Much work has focused on mTORC1 because it is selectively blocked by the microbial product rapamycin and its analogs (collectively designated rapamycins) that are approved for cancer treatment, and is frequently hyperactivated in malignant cells. In several, but not all human cancer cell lines, rapamycins increased IR cytotoxicity in vitro, apparently through multiple mechanisms, including the promotion of autophagic cell death. Rapamycins also potentiated fractionated RT in tumor xenograft models, in part by suppressing tumor angiogenesis. Synthetic kinase inhibitors that simultaneously target PI3K and both mTOR complexes also enhanced RT in vitro and in vivo, but with greater efficiency than rapamycins. These encouraging data have led to early clinical trials of rapamycins and catalytic mTOR inhibitors combined with RT in various cancers.

Keywords: Autophagy, cancer therapy, ionizing radiation, mTOR signaling, mTORC1, mTORC2, radiotherapy, radiosensitization, rapamycins

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