title: Combined targeting of JAK2 and Bcl-2/Bcl-xL to cure mutant JAK2-driven malignancies and overcome acquired resistance to JAK2 inhibitors.
abstract: To design rational therapies for JAK2-driven hematological malignancies, we functionally dissected the key survival pathways downstream of hyperactive JAK2. In tumors driven by mutant JAK2, Stat1, Stat3, Stat5, and the Pi3k and Mek/Erk pathways were constitutively active, and gene expression profiling of TEL-JAK2 T-ALL cells revealed the upregulation of prosurvival Bcl-2 family genes. Combining the Bcl-2/Bcl-xL inhibitor ABT-737 with JAK2 inhibitors mediated prolonged disease regressions and cures in mice bearing primary human and mouse JAK2 mutant tumors. Moreover, combined targeting of JAK2 and Bcl-2/Bcl-xL was able to circumvent and overcome acquired resistance to single-agent JAK2 inhibitor treatment. Thus, inhibiting the oncogenic JAK2 signaling network at two nodal points, at the initiating stage (JAK2) and the effector stage (Bcl-2/Bcl-xL), is highly effective and provides a clearly superior therapeutic benefit than targeting just one node. Therefore, we have defined a potentially curative treatment for hematological malignancies expressing constitutively active JAK2.
authors.affiliation: Cancer Therapeutics Program, The Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, 3002 VIC, Australia.
authors.forename: Michaela
authors.initials: M
authors.lastname: Waibel
authors.affiliation: Cancer Therapeutics Program, The Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, 3002 VIC, Australia.
authors.forename: Vanessa S
authors.initials: VS
authors.lastname: Solomon
authors.affiliation: Cancer Therapeutics Program, The Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, 3002 VIC, Australia.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Knight
authors.affiliation: Cancer Therapeutics Program, The Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, 3002 VIC, Australia.
authors.forename: Rachael A
authors.initials: RA
authors.lastname: Ralli
authors.affiliation: Cancer Therapeutics Program, The Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, 3002 VIC, Australia.
authors.forename: Sang-Kyu
authors.initials: SK
authors.lastname: Kim
authors.affiliation: Cancer Therapeutics Program, The Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, 3002 VIC, Australia.
authors.forename: Kellie-Marie
authors.initials: KM
authors.lastname: Banks
authors.affiliation: Cancer Therapeutics Program, The Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, 3002 VIC, Australia.
authors.forename: Eva
authors.initials: E
authors.lastname: Vidacs
authors.affiliation: Institut Curie, Centre Universitaire, Bat 110, 91405 Orsay, France; Centre National de la Recherche Scientifique, Unite Mixte de Recherche 3306, Centre Universitaire, Bat 110, 91405 Orsay, France; Institut National de la Sante et al Recherche Medicale, Unite 1005, Centre Universitaire, Bat 110, 91405 Orsay, France.
authors.forename: Clemence
authors.initials: C
authors.lastname: Virely
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, 2052 NSW, Australia.
authors.forename: Keith C S
authors.initials: KC
authors.lastname: Sia
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, 2052 NSW, Australia.
authors.forename: Lauryn S
authors.initials: LS
authors.lastname: Bracken
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Racquel
authors.initials: R
authors.lastname: Collins-Underwood
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Drenberg
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Laura B
authors.initials: LB
authors.lastname: Ramsey
authors.affiliation: Department of Medicine, Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Sara C
authors.initials: SC
authors.lastname: Meyer
authors.affiliation: Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, 3052 VIC, Australia.
authors.forename: Megumi
authors.initials: M
authors.lastname: Takiguchi
authors.affiliation: Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, 3052 VIC, Australia.
authors.forename: Ross A
authors.initials: RA
authors.lastname: Dickins
authors.affiliation: Department of Medicine, Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Ross
authors.initials: R
authors.lastname: Levine
authors.affiliation: Institut Curie, Centre Universitaire, Bat 110, 91405 Orsay, France; Centre National de la Recherche Scientifique, Unite Mixte de Recherche 3306, Centre Universitaire, Bat 110, 91405 Orsay, France; Institut National de la Sante et al Recherche Medicale, Unite 1005, Centre Universitaire, Bat 110, 91405 Orsay, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Ghysdael
authors.affiliation: Gurdon Institute and Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK; Department of Haematology, Cambridge Institute for Medical Research and Addenbrooke's Hospital, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Dawson
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, 2052 NSW, Australia.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Lock
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.affiliation: Cancer Therapeutics Program, The Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, 3002 VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, 3052 VIC, Australia. Electronic address: ricky.johnstone@petermac.org.
authors.forename: Ricky W
authors.initials: RW
authors.lastname: Johnstone
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D000072224:Bcl-2-Like Protein 11; D001713:Biphenyl Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009570:Nitriles; D009596:Nitrophenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D014183:Transplantation, Heterologous; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000235:genetics; D000096926:Benzenesulfonamides
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D001713:Biphenyl Compounds; D053614:Janus Kinase 2; D008565:Membrane Proteins; D009570:Nitriles; D009596:Nitrophenols; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D013449:Sulfonamides; D051020:bcl-X Protein; C501332:ABT-737; C000606775:BCL2L11 protein, human; C494812:Bcl2l1 protein, mouse; C000606776:Bcl2l11 protein, mouse; C522865:TG101209; D000096926:Benzenesulfonamides; C540383:ruxolitinib; C507926:Jak2 protein, mouse