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	Vol	Issue	Date	Pages	Journal Short Title
The Journal of experimental medicine	209	2	2012 Feb 13	259-73	J Exp Med

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	5	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
NVP-BVB808		BVB-808	JAK2 Inhibitor - ATP competitive 15	NVP-BVB808 is a selective ATP-competitive inhibitor of JAK2 (PMID: 22271575, PMID: 24504330).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
JAK2	E864K	missense	gain of function - predicted	JAK2 E864K lies within protein kinase domain 2 of the Jak2 protein (UniProt.org). E864K results in increased Jak2 and Stat5 phosphorylation and prevents apoptosis in the presence of a Jak inhibitor (PMID: 22916261), and has been described as a secondary drug resistance mutation in the context of other Jak2 activating mutations (PMID: 22916261, PMID: 22271575), and therefore, is predicted to lead to a gain of Jak2 protein function.	Y
JAK2	G935R	missense	gain of function - predicted	JAK2 G935R lies within protein kinase domain 2 of the Jak2 protein (UniProt.org). G935R results in increased Jak2 and Stat5 phosphorylation, prevents apoptosis in the presence of a Jak inhibitor (PMID: 22916261), and has been described as a secondary drug resistance mutation in the context of other Jak2 activating mutations (PMID: 22271575, PMID: 22916261), 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 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 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 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 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 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	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 G935R	hematologic cancer	resistant	Ruxolitinib	Preclinical - Cell culture	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
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 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