mTOR inhibitors are synergistic with methotrexate: an effective combination to treat acute lymphoblastic leukemia.
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.
Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, PA 19104, USA. teacheyd@email.chop.edu
David T
DT
Teachey
Cecilia
C
Sheen
Junior
J
Hall
Theresa
T
Ryan
Valerie I
VI
Brown
Jonathan
J
Fish
Gregor S D
GS
Reid
Alix E
AE
Seif
Robin
R
Norris
Yueh J
YJ
Chang
Martin
M
Carroll
Stephan A
SA
Grupp
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D056741:Cyclin D; D016213:Cyclins / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D008727:Methotrexate / Q000008:administration & dosage*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011494:Protein Kinases / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D014183:Transplantation, Heterologous
D000964:Antimetabolites, Antineoplastic; D056741:Cyclin D; D016213:Cyclins; D047428:Protein Kinase Inhibitors; D013762:Tetrahydrofolate Dehydrogenase; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D008727:Methotrexate