Lymphocyte Specific Protein Tyrosine Kinase p56(lck); Dasatinib; temsirolimus; Tyrosine; Protein Kinase Inhibitors; Mechanistic Target of Rapamycin Complex 1; Receptors, Antigen, T-Cell; MTOR protein, human; Child; Humans; Mice; Animals; Dasatinib/pharmacology; Dasatinib/therapeutic use; Zebrafish/metabolism; Cell Line, Tumor; Signal Transduction; Protein Kinase Inhibitors/pharmacology; Protein Kinase Inhibitors/therapeutic use; Mechanistic Target of Rapamycin Complex 1/metabolism; Receptors, Antigen, T-Cell/therapeutic use; T-Lymphocytes/metabolism; Recurrence; Mammals/metabolism; Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/metabolism; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism; Mammals; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; T-Lymphocytes; Zebrafish; Biochemistry; Immunology; Hematology; Cell Biology
Abstract :
[en] Relapse and refractory T-cell acute lymphoblastic leukemia (T-ALL) has a poor prognosis, and new combination therapies are sorely needed. Here, we used an ex vivo high-throughput screening platform to identify drug combinations that kill zebrafish T-ALL and then validated top drug combinations for preclinical efficacy in human disease. This work uncovered potent drug synergies between AKT/mTORC1 (mammalian target of rapamycin complex 1) inhibitors and the general tyrosine kinase inhibitor dasatinib. Importantly, these same drug combinations effectively killed a subset of relapse and dexamethasone-resistant zebrafish T-ALL. Clinical trials are currently underway using the combination of mTORC1 inhibitor temsirolimus and dasatinib in other pediatric cancer indications, leading us to prioritize this therapy for preclinical testing. This combination effectively curbed T-ALL growth in human cell lines and primary human T-ALL and was well tolerated and effective in suppressing leukemia growth in patient-derived xenografts (PDX) grown in mice. Mechanistically, dasatinib inhibited phosphorylation and activation of the lymphocyte-specific protein tyrosine kinase (LCK) to blunt the T-cell receptor (TCR) signaling pathway, and when complexed with mTORC1 inhibition, induced potent T-ALL cell killing through reducing MCL-1 protein expression. In total, our work uncovered unexpected roles for the LCK kinase and its regulation of downstream TCR signaling in suppressing apoptosis and driving continued leukemia growth. Analysis of a wide array of primary human T-ALLs and PDXs grown in mice suggest that combination of temsirolimus and dasatinib treatment will be efficacious for a large fraction of human T-ALLs.
Disciplines :
Oncology
Author, co-author :
Laukkanen, Saara ✱; Tampere Center for Child, Adolescent, and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
Bacquelaine Veloso, Alexandra ✱; Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Virologie - Immunologie ; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA ; Harvard Stem Cell Institute, Boston, MA ; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA
Yan, Chuan; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA ; Harvard Stem Cell Institute, Boston, MA ; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA
Oksa, Laura ; Tampere Center for Child, Adolescent, and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
Alpert, Eric J ; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA ; Harvard Stem Cell Institute, Boston, MA ; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA
Do, Daniel; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA ; Harvard Stem Cell Institute, Boston, MA ; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA
Hyvärinen, Noora; Tampere Center for Child, Adolescent, and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
McCarthy, Karin; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA ; Harvard Stem Cell Institute, Boston, MA ; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA
Adhikari, Abhinav ; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA ; Harvard Stem Cell Institute, Boston, MA ; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA
Yang, Qiqi ; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA ; Harvard Stem Cell Institute, Boston, MA ; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA
Iyer, Sowmya; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA ; Harvard Stem Cell Institute, Boston, MA ; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA
Garcia, Sara P ; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA ; Harvard Stem Cell Institute, Boston, MA ; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA
Pello, Annukka ; Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland
Ruokoranta, Tanja; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
Moisio, Sanni; The Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland
Adhikari, Sadiksha ; Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland
Yoder, Jeffrey A ; Department of Molecular Biomedical Sciences, Comparative Medicine Institute, and Center for Human Health and the Environment, North Carolina State University, Raleigh, NC
Gallagher, Kayleigh; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA
Whelton, Lauren; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA ; Harvard Stem Cell Institute, Boston, MA ; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA
Allen, James R ; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA ; Harvard Stem Cell Institute, Boston, MA ; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA
Jin, Alex H ; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA ; Harvard Stem Cell Institute, Boston, MA ; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA
Loontiens, Siebe ; Cancer Research Institute Ghent and Center for Medical Genetics, Ghent, Belgium
Heinäniemi, Merja ; The Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland
Kelliher, Michelle; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA
Heckman, Caroline A ; Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland
Lohi, Olli ✱; Tampere Center for Child, Adolescent, and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland ; Tampere University Hospital, Tays Cancer Center, Tampere, Finland
Langenau, David M ✱; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA ; Harvard Stem Cell Institute, Boston, MA ; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA
The authors thank the Finnish IT Center for Science and UEF Bioinformatics Center, University of Eastern Finland, Finland, for computation resources; Eini Eskola for assistance in laboratory work; David Weinstock for kindly providing PDX samples; Tony Letai for advice on apoptotic pathways to analyze in treated T-ALLs; Brian Millet and Daniel O'Neill for thoughtful discussions; and the patients for providing samples for our studies. The FIMM Technology Center High Throughput Biomedicine Unit and Sequencing Laboratory are acknowledged for their expert technical support. This work was supported by National Institutes of Health grant R01CA211734 (D.M.L.), the Massachusetts General Hospital Research Scholar Award (D.M.L.), Academy of Finland (O.L. and M.H. 321553; O.L. 310106), Cancer Foundation Finland (O.L. M.H. C.A.H.), Jane and Aatos Erkko Foundation (O.L. M.H.), Sigrid Juselius Foundation (O.L. M.H. C.A.H.), Aamu Foundation (O.L.), Finnish Hematology Association (S.Laukkanen), Finnish Blood Disease Research Foundation (S.Laukkanen), and the Competitive State Research Financing of the Expert Responsibility Area of Tampere University Hospital (O.L. 9V033 and 9X027). FIMM High Throughput Biomedicine Unit and Sequencing Laboratory are financially supported by the University of Helsinki (HiLife) and Biocenter Finland. Contribution: D.M.L. O.L. S. Laukkanen, and A.V. conceived the study. S. Loontiens, A.V. C.Y. L.O. D.D. A.H.J. E.J.A. L.W. J.R.A. K.M. A.A. and N.H. conducted experiments. S. Loontiens and J.Y. produced gateway plasmids. S.I, S.M. S.A. and S.P.G. analyzed sequencing data. C.Y. K.G. and M.K. advised in animal experiments. A.P. assisted with primary patient samples. T.R. advised with the experimental design and data analysis of primary patient samples. C.A.H. provided primary patient samples and advised with the data. M.H. advised with data. D.L. and O.L. supervised the study. All authors reviewed and accepted the manuscript.This work was supported by National Institutes of Health grant R01CA211734 (D.M.L.), the Massachusetts General Hospital Research Scholar Award (D.M.L.), Academy of Finland (O.L. and M.H., 321553; O.L., 310106), Cancer Foundation Finland (O.L., M.H., C.A.H.), Jane and Aatos Erkko Foundation (O.L., M.H.), Sigrid Juselius Foundation (O.L., M.H., C.A.H.), Aamu Foundation (O.L.), Finnish Hematology Association (S.Laukkanen), Finnish Blood Disease Research Foundation (S.Laukkanen), and the Competitive State Research Financing of the Expert Responsibility Area of Tampere University Hospital (O.L., 9V033 and 9X027). FIMM High Throughput Biomedicine Unit and Sequencing Laboratory are financially supported by the University of Helsinki (HiLife) and Biocenter Finland.
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