Reference Detail

Ref Type Journal Article
PMID (22271575)
Authors Weigert O, Lane AA, Bird L, Kopp N, Chapuy B, van Bodegom D, Toms AV, Marubayashi S, Christie AL, McKeown M, Paranal RM, Bradner JE, Yoda A, Gaul C, Vangrevelinghe E, Romanet V, Murakami M, Tiedt R, Ebel N, Evrot E, De Pover A, Regnier CH, Erdmann D, Hofmann F, Eck MJ, Sallan SE, Levine RL, Kung AL, Baffert F, Radimerski T, Weinstock DM
Title Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition.
Journal The Journal of experimental medicine
Vol 209
Issue 2
Date 2012 Feb 13
URL
Abstract Text Enzymatic inhibitors of Janus kinase 2 (JAK2) are in clinical development for the treatment of myeloproliferative neoplasms (MPNs), B cell acute lymphoblastic leukemia (B-ALL) with rearrangements of the cytokine receptor subunit cytokine receptor-like factor 2 (CRLF2), and other tumors with constitutive JAK2 signaling. In this study, we identify G935R, Y931C, and E864K mutations within the JAK2 kinase domain that confer resistance across a panel of JAK inhibitors, whether present in cis with JAK2 V617F (observed in MPNs) or JAK2 R683G (observed in B-ALL). G935R, Y931C, and E864K do not reduce the sensitivity of JAK2-dependent cells to inhibitors of heat shock protein 90 (HSP90), which promote the degradation of both wild-type and mutant JAK2. HSP90 inhibitors were 100-1,000-fold more potent against CRLF2-rearranged B-ALL cells, which correlated with JAK2 degradation and more extensive blockade of JAK2/STAT5, MAP kinase, and AKT signaling. In addition, the HSP90 inhibitor AUY922 prolonged survival of mice xenografted with primary human CRLF2-rearranged B-ALL further than an enzymatic JAK2 inhibitor. Thus, HSP90 is a promising therapeutic target in JAK2-driven cancers, including those with genetic resistance to JAK enzymatic inhibitors.

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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
NVP-BVB808 NVP-BVB808 4 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
NVP-BVB808 JAK2 Inhibitor - ATP competitive 14 NVP-BVB808 is a selective ATP-competitive inhibitor of JAK2 (PMID: 22271575).
Variant Impact Protein Effect Variant Description Associated with drug Resistance
E864K missense gain of function - predicted JAK2 E864K lies within the JH1 protein kinase domain 2 of the Jak2 protein (UniProt.org). E864K is predicted to confer a gain of function to the Jak2 protein, as demonstrated by increased Jak2 and Stat5 phosphorylation and also prevents apoptosis in the presence of a Jak inhibitor (PMID: 22916261) and therefore, has been described as a secondary drug resistance mutation in the context of other Jak2 activating mutations (PMID: 22916261, PMID: 22271575). Y
G935R missense gain of function - predicted JAK2 G935R lies within the JH1 protein kinase domain 2 of the Jak2 protein (UniProt.org). G935R is predicted to confer a gain of function to the Jak2 protein, as demonstrated by increased Jak2 and Stat5 phosphorylation and also prevents apoptosis in the presence of a Jak inhibitor (PMID: 22916261) and therefore, has been described as a secondary drug resistance mutation in the context of other Jak2 activating mutations (PMID: 22271575, PMID: 22916261). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
JAK2 R683G JAK2 E864K cancer resistant NVP-BSK805 Preclinical - Cell culture Actionable In a preclinical study, cells expressing the JAK2 R683G/E864K double mutation demonstrated resistance to NVP-BSK805 in culture (PMID: 22271575). 22271575
JAK2 V617F JAK2 G935R hematologic cancer resistant NVP-BVB808 Preclinical Actionable In a preclinical study, immune cells expressing the JAK2 V617F and JAK2 G935R double mutation demonstrated resistance to NVP-BVB808 in culture (PMID: 22271575). 22271575
JAK2 V617F JAK2 G935R hematologic cancer resistant NVP-BSK805 Preclinical - Cell culture Actionable In a preclinical study, immune cells expressing the JAK2 V617F and JAK2 G935R double mutation demonstrated resistance to NVP-BSK805 in culture (PMID: 22271575). 22271575
JAK2 V617F JAK2 E864K hematologic cancer resistant NVP-BVB808 Preclinical Actionable In a preclinical study, immune cells expressing the JAK2 V617F and JAK2 E864K double mutation demonstrated resistance to NVP-BVB808 in culture (PMID: 22271575). 22271575
JAK2 R683G JAK2 E864K cancer resistant NVP-BVB808 Preclinical Actionable In a preclinical study, cells expressing the JAK2 R683G/E864K double mutation demonstrated resistance to NVP-BVB808 in culture (PMID: 22271575). 22271575
JAK2 R683G JAK2 G935R cancer resistant Ruxolitinib Preclinical Actionable In a preclinical study, cells expressing the JAK2 R683G/G935R double mutation demonstrated resistance to Jakafi (Ruxolitinib) in culture (PMID: 22271575). 22271575
JAK2 V617F JAK2 E864K hematologic cancer resistant NVP-BSK805 Preclinical - Cell culture Actionable In a preclinical study, immune cells expressing the JAK2 V617F and JAK2 E864K double mutation demonstrated resistance to NVP-BSK805 in culture (PMID: 22271575). 22271575
JAK2 R683G JAK2 G935R cancer resistant NVP-BVB808 Preclinical Actionable In a preclinical study, cells expressing the JAK2 R683G/G935R double mutation demonstrated resistance to NVP-BVB808 in culture (PMID: 22271575). 22271575
JAK2 R683G JAK2 G935R cancer resistant NVP-BSK805 Preclinical - Cell culture Actionable In a preclinical study, cells expressing the JAK2 R683G/G935R double mutation demonstrated resistance to NVP-BSK805 in culture (PMID: 22271575). 22271575
JAK2 V617F JAK2 G935R hematologic cancer resistant Ruxolitinib Preclinical Actionable In a preclinical study, immune cells expressing the JAK2 V617F and JAK2 G935R double mutation demonstrated resistance to Jakafi (Ruxolitinib) in culture (PMID: 22271575). 22271575