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 Blood, 1 September 2008, Vol. 112, No. 5, pp. 2020-2023.
Prepublished online as a Blood First Edition Paper on June 10, 2008; DOI 10.1182/blood-2008-02-137141.

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NEOPLASIA

Brief Report

mTOR inhibitors are synergistic with methotrexate: an effective combination to treat acute lymphoblastic leukemia

David T. Teachey1, Cecilia Sheen1, Junior Hall1, Theresa Ryan1, Valerie I. Brown1, Jonathan Fish1, Gregor S. D. Reid1, Alix E. Seif1, Robin Norris1, Yueh J. Chang1, Martin Carroll2, and Stephan A. Grupp1,3

1 Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, PA; 2 Division of Hematology and Oncology, University of Pennsylvania, Philadelphia; and 3 Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, PA

We have previously demonstrated that mTOR inhibitors (MTIs) are active in preclinical models of acute lymphoblastic leukemia (ALL). MTIs may increase degradation of cyclin D1, a protein involved in dihydrofolate reductase (DHFR) synthesis. Because resistance to methotrexate may correlate with high DHFR expression, we hypothesized MTIs may increase sensitivity of ALL to methotrexate through decreasing DHFR by increasing turn-over of cyclin D1. We tested this hypothesis using multiple ALL cell lines and nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice xenografted with human ALL. We found MTIs and methotrexate were synergistic in combination in vitro and in vivo. Mice treated with both drugs went into a complete and durable remission whereas single agent treatment caused an initial partial response that ultimately progressed. ALL cells treated with MTIs had markedly decreased expression of DHFR and cyclin D1, providing a novel mechanistic explanation for a combined effect. We found methotrexate and MTIs are an effective and potentially synergistic combination in ALL.


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