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.
Teachey
David T
DT
Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, PA 19104, USA. teacheyd@email.chop.edu
Sheen
Cecilia
C
Hall
Junior
J
Ryan
Theresa
T
Brown
Valerie I
VI
Fish
Jonathan
J
Reid
Gregor S D
GS
Seif
Alix E
AE
Norris
Robin
R
Chang
Yueh J
YJ
Carroll
Martin
M
Grupp
Stephan A
SA
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