Effects of combined inhibition of MEK and mTOR on downstream signaling and tumor growth in pancreatic cancer xenograft models.
The ERK and mTOR pathways show multiple interconnections that coordinate growth activation and the regulation of protein translation. Although drugs that target these pathways appear to have limited anti-cancer effects as single agents, we hypothesized that the monotherapy anticancer efficacy of these agents could be enhanced by their combination. The MEK inhibitor AZD6244 (ARRY-142886) and the mTOR inhibitor rapamycin were tested as single agents and in combination, using BxPC-3 and MIA PaCa-2 pancreatic cancer models in vivo. In both models, S6 ribosomal protein was almost completely inhibited with combined treatment, but only partially inhibited with the single agents. In addition, 48 h treatment with the drug combination produced greater apoptosis, revealed by caspase 3 cleavage, and growth inhibition measured using bromodeoxyuridine incorporation, compared to the single agents. AZD6244 but not rapamycin exhibited a significant anti-angiogenic effect, as shown by tumor VEGF ELISA assay and CD31 analysis. Plasma and tumor pharmacokinetic analyses indicated that AZD6244 accumulates in tumor tissue at concentrations that produce target inhibition and cell cycle arrest in vitro. In chronic dosing experiments, the drug combination was well tolerated, and showed greater growth inhibition compared to the single agents. These results are consistent with the hypothesis that ERK and mTOR signaling interact at multiple levels to regulate tumor growth in vivo, and support the testing of MEK plus mTOR inhibitor combinations in pancreatic cancer patients.
Chang
Qing
Q
Division of Applied Molecular Oncology, Ontario Cancer Institute/Princess Margaret Hospital, University of Toronto, Toronto, ON, Canada.
Chen
Eric
E
Hedley
David W
DW
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
C517975:AZD 6244; D001562:Benzimidazoles; D047908:Intracellular Signaling Peptides and Proteins; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020123:Sirolimus