title: Tumor-specific HSP90 inhibition as a therapeutic approach in JAK-mutant acute lymphoblastic leukemias.
abstract: The development of the dual Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib for the treatment of myeloproliferative neoplasms (MPNs) has led to studies of ruxolitinib in other clinical contexts, including JAK-mutated acute lymphoblastic leukemia (ALL). However, the limited ability of JAK inhibition to induce molecular or clinicopathological responses in MPNs suggests a need for development of better therapies for JAK kinase-dependent malignancies. Here, we demonstrate that heat shock protein 90 (HSP90) inhibition using a purine-scaffold HSP90 inhibitor in early clinical development is an effective therapeutic approach in JAK-dependent ALL and can overcome persistence to JAK-inhibitor therapy in ALL cells.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Pediatrics, Division of Hematology/Oncology, Weill Cornell Medical College, New York, NY;
authors.forename: Nicole
authors.initials: N
authors.lastname: Kucine
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY;
authors.forename: Sachie
authors.initials: S
authors.lastname: Marubayashi
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY; Gerstner Sloan Kettering Graduate School in Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY;
authors.forename: Neha
authors.initials: N
authors.lastname: Bhagwat
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY;
authors.forename: Efthymia
authors.initials: E
authors.lastname: Papalexi
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY;
authors.forename: Priya
authors.initials: P
authors.lastname: Koppikar
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY;
authors.forename: Marta
authors.initials: M
authors.lastname: Sanchez Martin
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY;
authors.forename: Lauren
authors.initials: L
authors.lastname: Dong
authors.affiliation: Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY;
authors.forename: Marty S
authors.initials: MS
authors.lastname: Tallman
authors.affiliation: Division of Hemato-Oncology, Department of Medicine (Oncology), Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY;
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Paietta
authors.affiliation: Foundation Medicine, Cambridge, MA;
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Foundation Medicine, Cambridge, MA;
authors.forename: Jie
authors.initials: J
authors.lastname: He
authors.affiliation: Foundation Medicine, Cambridge, MA;
authors.forename: Doron
authors.initials: D
authors.lastname: Lipson
authors.affiliation: Foundation Medicine, Cambridge, MA;
authors.forename: Phil
authors.initials: P
authors.lastname: Stephens
authors.affiliation: Foundation Medicine, Cambridge, MA;
authors.forename: Vince
authors.initials: V
authors.lastname: Miller
authors.affiliation: Department of Hematology and Bone Marrow Transplantation, The Rambam Medical Center, Haifa, Israel;
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Rowe
authors.affiliation: Department of Pathology, Icahn School of Medicine, Mount Sinai, New York, NY;
authors.forename: Julie
authors.initials: J
authors.lastname: Teruya-Feldstein
authors.affiliation: Department of Pathology and Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, TN; and.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY;
authors.forename: Adolfo A
authors.initials: AA
authors.lastname: Ferrando
authors.affiliation: Cancer Biology and Genetics Program, Center for Epigenetics Research, and.
authors.forename: Andrei
authors.initials: A
authors.lastname: Krivtsov
authors.affiliation: Cancer Biology and Genetics Program, Center for Epigenetics Research, and.
authors.forename: Scott
authors.initials: S
authors.lastname: Armstrong
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY;
authors.forename: Laura
authors.initials: L
authors.lastname: Leung
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Stefan O
authors.initials: SO
authors.lastname: Ochiana
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Chiosis
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY; Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY; Center for Epigenetics Research, and.
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY;
authors.forename: Maria
authors.initials: M
authors.lastname: Kleppe
mesh_terms: D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology*; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D009154:Mutation; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011687:Purines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D052117:Benzodioxoles; D018841:HSP90 Heat-Shock Proteins; D009363:Neoplasm Proteins; D011687:Purines; C526550:9H-purine-9-propanamine, 6-amino-8-((6-iodo-1,3-benzodioxol-5-yl)thio)-N-(1-methylethyl)-; C507904:JAK1 protein, human; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2