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Ref Type Journal Article
PMID (26175414)
Authors Wu SC, Li LS, Kopp N, Montero J, Chapuy B, Yoda A, Christie AL, Liu H, Christodoulou A, van Bodegom D, van der Zwet J, Layer JV, Tivey T, Lane AA, Ryan JA, Ng SY, DeAngelo DJ, Stone RM, Steensma D, Wadleigh M, Harris M, Mandon E, Ebel N, Andraos R, Romanet V, Dölemeyer A, Sterker D, Zender M, Rodig SJ, Murakami M, Hofmann F, Kuo F, Eck MJ, Silverman LB, Sallan SE, Letai A, Baffert F, Vangrevelinghe E, Radimerski T, Gaul C, Weinstock DM
Title Activity of the Type II JAK2 Inhibitor CHZ868 in B Cell Acute Lymphoblastic Leukemia.
Journal Vol Issue Date Pages Journal Short Title
Cancer cell 28 1 2015 Jul 13 29-41 Cancer Cell
URL
Abstract Text A variety of cancers depend on JAK2 signaling, including the high-risk subset of B cell acute lymphoblastic leukemias (B-ALLs) with CRLF2 rearrangements. Type I JAK2 inhibitors induce paradoxical JAK2 hyperphosphorylation in these leukemias and have limited activity. To improve the efficacy of JAK2 inhibition in B-ALL, we developed the type II inhibitor CHZ868, which stabilizes JAK2 in an inactive conformation. CHZ868 potently suppressed the growth of CRLF2-rearranged human B-ALL cells, abrogated JAK2 signaling, and improved survival in mice with human or murine B-ALL. CHZ868 and dexamethasone synergistically induced apoptosis in JAK2-dependent B-ALLs and further improved in vivo survival compared to CHZ868 alone. These data support the testing of type II JAK2 inhibition in patients with JAK2-dependent leukemias and other disorders.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
JAK2 L884P missense gain of function - predicted JAK2 L884P lies within protein kinase domain 2 of the Jak2 protein (UniProt.org). L884P results in cytokine-independent growth in culture (PMID: 26175414), and has been demonstrated to confer resistance to Jak2 inhibitors in cultured cells (PMID: 26175414, PMID: 37290440), and therefore, is predicted to lead to a gain of Jak2 protein function. Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
JAK2 R683G JAK2 L884P hematologic cancer resistant CHZ868 Preclinical - Cell culture Actionable In a preclinical study, cells expressing JAK2 R683G and L884P were resistant to CHZ868 in culture (PMID: 26175414). 26175414