title: Arsenic trioxide overcomes rapamycin-induced feedback activation of AKT and ERK signaling to enhance the anti-tumor effects in breast cancer.
abstract: Inhibitors of the mammalian target of rapamycin (mTORi) have clinical activity; however, the benefits of mTOR inhibition by rapamycin and rapamycin-derivatives (rapalogs) may be limited by a feedback mechanism that results in AKT activation. Increased AKT activity resulting from mTOR inhibition can be a result of increased signaling via the mTOR complex, TORC2. Previously, we published that arsenic trioxide (ATO) inhibits AKT activity and in some cases, decreases AKT protein expression. Therefore, we propose that combining ATO and rapamycin may circumvent the AKT feedback loop and increase the anti-tumor effects. Using a panel of breast cancer cell lines, we find that ATO, at clinically-achievable doses, can enhance the inhibitory activity of the mTORi temsirolimus. In all cell lines, temsirolimus treatment resulted in AKT activation, which was decreased by concomitant ATO treatment only in those cell lines where ATO enhanced growth inhibition. Treatment with rapalog also results in activated ERK signaling, which is decreased with ATO co-treatment in all cell lines tested. We next tested the toxicity and efficacy of rapamycin plus ATO combination therapy in a MDA-MB-468 breast cancer xenograft model. The drug combination was well-tolerated, and rapamycin did not increase ATO-induced liver enzyme levels. In addition, combination of these drugs was significantly more effective at inhibiting tumor growth compared to individual drug treatments, which corresponded with diminished phospho-Akt and phospho-ERK levels when compared with rapamycin-treated tumors. Therefore, we propose that combining ATO and mTORi may overcome the feedback loop by decreasing activation of the MAPK and AKT signaling pathways.
authors.affiliation: Lady Davis Institute for Medical Research, McGill University, Montreal, Canada.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Guilbert
authors.affiliation: Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Canada.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Annis
authors.affiliation: Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Canada.
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Canada.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Siegel
authors.affiliation: Lady Davis Institute for Medical Research, McGill University, Montreal, Canada ; Department of Oncology, McGill University, Montreal, Canada.
authors.forename: Wilson H
authors.initials: WH
authors.lastname: Miller
authors.affiliation: Lady Davis Institute for Medical Research, McGill University, Montreal, Canada ; Department of Oncology, McGill University, Montreal, Canada.
authors.forename: Koren K
authors.initials: KK
authors.lastname: Mann
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D025461:Feedback, Physiological / Q000187:drug effects*; D006801:Humans; D051379:Mice; D010087:Oxides / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D000077237:Arsenic Trioxide; D020123:Sirolimus