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Ref Type

Journal Article

PMID

(21926964)

Authors

Deshpande A, Reddy MM, Schade GO, Ray A, Chowdary TK, Griffin JD, Sattler M

Title

Kinase domain mutations confer resistance to novel inhibitors targeting JAK2V617F in myeloproliferative neoplasms.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Leukemia	26	4	2012 Apr	708-15	Leukemia

URL

Abstract Text

The transforming JAK2V617F kinase is frequently associated with myeloproliferative neoplasms and thought to be instrumental for the overproduction of myeloid lineage cells. Several small molecule drugs targeting JAK2 are currently in clinical development for treatment in these diseases. We performed a high-throughput in vitro screen to identify point mutations in JAK2V617F that would be predicted to have potential clinical relevance and associated with drug resistance to the JAK2 inhibitor ruxolitinib (INCB018424). Seven libraries of mutagenized JAK2V617F cDNA were screened to specifically identify mutations in the predicted drug-binding region that would confer resistance to ruxolitinib, using a BaF3 cell-based assay. We identified five different non-synonymous point mutations that conferred drug resistance. Cells containing mutations had a 9- to 33-fold higher EC(50) for ruxolitinib compared with native JAK2V617F. Our results further indicated that these mutations also conferred cross-resistance to all JAK2 kinase inhibitors tested, including AZD1480, TG101348, lestaurtinib (CEP-701) and CYT-387. Surprisingly, introduction of the 'gatekeeper' mutation (M929I) in JAK2V617F affected only ruxolitinib sensitivity (fourfold increase in EC(50)). These results suggest that JAK2 inhibitors currently in clinical trials may be prone to resistance as a result of point mutations and caution should be exercised when administering these drugs.

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Molecular Profile	Treatment Approach
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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
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Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
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Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
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Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
JAK2	M929I	missense	gain of function - predicted	JAK2 M929I is a gatekeeper mutation that lies within protein kinase domain 2 of the Jak2 protein (UniProt.org). M929I demonstrates increased Jak2 and Stat5 phosphorylation (PMID: 22916261), and has been described as a secondary drug resistance mutation in the context of other Jak2 activating mutations (PMID: 22916261, PMID: 23823659, PMID: 21926964), and therefore, is predicted to lead to a gain of Jak2 protein function.	Y
JAK2	R938L	missense	unknown	JAK2 R938L lies within protein kinase domain 2 of the Jak2 protein (UniProt.org). R938L has been demonstrated to occur as a secondary drug resistance mutation (PMID: 21926964), but has not been biochemically characterized and therefore, its effect on Jak2 protein function is unknown (PubMed, Mar 2025).	Y
JAK2	I960V	missense	unknown	JAK2 I960V lies within protein kinase domain 2 of the Jak2 protein (UniProt.org). I960V has been described as a secondary drug resistance mutation in the context of JAK2 V617F (PMID: 23009939, PMID: 21926964), but has not been biochemically characterized and therefore, its effect on Jak2 protein function is unknown (PubMed, Feb 2025).	Y
JAK2	E985K	missense	unknown	JAK2 E985K lies within protein kinase domain 2 of the Jak2 protein (UniProt.org). E985K has been demonstrated to confer resistance to Jak inhibitors in the context of complex JAK2 mutations (PMID: 21926964), but has not been biochemically characterized and therefore, its effect on Jak2 protein function is unknown (PubMed, Feb 2025).	Y

Showing 1 to 4 of 4 entries

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Showing 1 to 29 of 29 entries

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
JAK2 V617F JAK2 E985K	hematologic cancer	resistant	AZD1480	Preclinical - Cell culture	Actionable	In a preclinical study, cells expressing the JAK2 V617F and JAK2 E985K double mutation demonstrated resistance to AZD1480 in culture (PMID: 21926964).	21926964
JAK2 V617F JAK2 E985K	hematologic cancer	resistant	Momelotinib	Preclinical - Cell culture	Actionable	In a preclinical study, cells expressing the JAK2 V617F and JAK2 E985K double mutation demonstrated resistance to Momelotinib in culture (PMID: 21926964).	21926964
JAK2 V617F JAK2 E985K	hematologic cancer	resistant	Lestaurtinib	Preclinical - Cell culture	Actionable	In a preclinical study, cells expressing the JAK2 V617F and JAK2 E985K double mutation demonstrated resistance to Lestaurtinib (CEP-701) in culture (PMID: 21926964).	21926964
JAK2 V617F JAK2 E985K	hematologic cancer	resistant	Fedratinib	Preclinical - Cell culture	Actionable	In a preclinical study, cells expressing the JAK2 V617F and JAK2 E985K double mutation demonstrated resistance to Inrebic (fedratinib) in culture (PMID: 21926964).	21926964
JAK2 V617F JAK2 G935R	hematologic cancer	resistant	AZD1480	Preclinical - Cell culture	Actionable	In a preclinical study, cells expressing the JAK2 V617F and JAK2 G935R double mutation demonstrated resistance to AZD1480 in culture (PMID: 21926964).	21926964
JAK2 V617F JAK2 G935R	hematologic cancer	resistant	Lestaurtinib	Preclinical - Cell culture	Actionable	In a preclinical study, cells expressing the JAK2 V617F and JAK2 G935R double mutation demonstrated resistance to Lestaurtinib (CEP-701) in culture (PMID: 21926964).	21926964
JAK2 V617F JAK2 G935R	hematologic cancer	resistant	Fedratinib	Preclinical - Cell culture	Actionable	In a preclinical study, cells expressing the JAK2 V617F and JAK2 G935R double mutation demonstrated resistance to Inrebic (fedratinib) in culture (PMID: 21926964).	21926964
JAK2 V617F JAK2 G935R	hematologic cancer	resistant	Momelotinib	Preclinical - Cell culture	Actionable	In a preclinical study, cells expressing the JAK2 V617F and JAK2 G935R double mutation demonstrated resistance to Momelotinib in culture (PMID: 21926964).	21926964
JAK2 V617F JAK2 I960V	hematologic cancer	resistant	Fedratinib	Preclinical - Cell culture	Actionable	In a preclinical study, immune cells expressing the JAK2 V617F and JAK2 I960V double mutation demonstrated resistance to Inrebic (fedratinib) in culture (PMID: 21926964).	21926964
JAK2 V617F JAK2 M929I	hematologic cancer	predicted - sensitive	Fedratinib	Preclinical - Cell culture	Actionable	In a preclinical study, cells expressing the JAK2 V617F and JAK2 M929I double mutation were sensitive to treatment with Inrebic (fedratinib) in culture, demonstrating growth inhibition (PMID: 21926964).	21926964
JAK2 V617F JAK2 M929I	hematologic cancer	predicted - sensitive	Momelotinib	Preclinical - Cell culture	Actionable	In a preclinical study, cells expressing the JAK2 V617F and JAK2 M929I double mutation were sensitive to treatment with Momelotinib in culture, demonstrating growth inhibition (PMID: 21926964).	21926964
JAK2 V617F JAK2 M929I	hematologic cancer	predicted - sensitive	AZD1480	Preclinical - Cell culture	Actionable	In a preclinical study, cells expressing the JAK2 V617F and JAK2 M929I double mutation were sensitive to treatment with AZD1480 in culture, demonstrating growth inhibition (PMID: 21926964).	21926964
JAK2 V617F JAK2 M929I	hematologic cancer	predicted - sensitive	Lestaurtinib	Preclinical - Cell culture	Actionable	In a preclinical study, cells expressing the JAK2 V617F and JAK2 M929I double mutation were sensitive to treatment with Lestaurtinib (CEP-701) in culture, demonstrating growth inhibition (PMID: 21926964).	21926964
JAK2 V617F JAK2 R938L	hematologic cancer	resistant	Fedratinib	Preclinical - Cell culture	Actionable	In a preclinical study, immune cells expressing the JAK2 V617F and JAK2 R938L double mutation demonstrated resistance to Inrebic (fedratinib) in culture (PMID: 21926964).	21926964
JAK2 V617F JAK2 Y931C	hematologic cancer	resistant	AZD1480	Preclinical - Cell culture	Actionable	In a preclinical study, cells expressing the JAK2 V617F and JAK2 Y931C double mutation demonstrated resistance to AZD1480 in culture (PMID: 21926964).	21926964
JAK2 V617F JAK2 Y931C	hematologic cancer	resistant	Fedratinib	Preclinical - Cell culture	Actionable	In a preclinical study, cells expressing the JAK2 V617F and JAK2 Y931C double mutation demonstrated resistance to Inrebic (fedratinib) in culture (PMID: 21926964).	21926964
JAK2 V617F JAK2 Y931C	hematologic cancer	resistant	Momelotinib	Preclinical - Cell culture	Actionable	In a preclinical study, cells expressing the JAK2 V617F and JAK2 Y931C double mutation demonstrated resistance to Momelotinib in culture (PMID: 21926964).	21926964
JAK2 V617F JAK2 Y931C	hematologic cancer	resistant	Ruxolitinib	Preclinical - Cell culture	Actionable	In a preclinical study, cells expressing the JAK2 V617F and JAK2 Y931C double mutation demonstrated resistance to Jakafi (Ruxolitinib) in culture (PMID: 21926964).	21926964
JAK2 V617F JAK2 Y931C	hematologic cancer	resistant	Lestaurtinib	Preclinical - Cell culture	Actionable	In a preclinical study, cells expressing the JAK2 V617F and JAK2 Y931C double mutation demonstrated resistance to Lestaurtinib (CEP-701) in culture (PMID: 21926964).	21926964
JAK2 V617F JAK2 E985K	hematologic cancer	resistant	Ruxolitinib	Preclinical	Actionable	In a preclinical study, immune cells expressing the JAK2 V617F and JAK2 E985K double mutation demonstrated resistance to Jakafi (Ruxolitinib) in culture (PMID: 21926964).	21926964
JAK2 V617F JAK2 I960V	hematologic cancer	resistant	Ruxolitinib	Preclinical	Actionable	In a preclinical study, immune cells expressing the JAK2 V617F and JAK2 I960V double mutation demonstrated resistance to Jakafi (Ruxolitinib) in culture (PMID: 21926964).	21926964
JAK2 V617F JAK2 I960V	hematologic cancer	resistant	AZD1480	Preclinical	Actionable	In a preclinical study, immune cells expressing the JAK2 V617F and JAK2 I960V double mutation demonstrated resistance to AZD1480 in culture (PMID: 21926964).	21926964
JAK2 V617F JAK2 I960V	hematologic cancer	resistant	Lestaurtinib	Preclinical	Actionable	In a preclinical study, immune cells expressing the JAK2 V617F and JAK2 I960V double mutation demonstrated resistance to Lestaurtinib (CEP-701) in culture (PMID: 21926964).	21926964
JAK2 V617F JAK2 I960V	hematologic cancer	resistant	Momelotinib	Preclinical	Actionable	In a preclinical study, immune cells expressing the JAK2 V617F and JAK2 I960V double mutation demonstrated resistance to Momelotinib in culture (PMID: 21926964).	21926964
JAK2 V617F JAK2 M929I	hematologic cancer	resistant	Ruxolitinib	Preclinical	Actionable	In a preclinical study, immune cells expressing the JAK2 V617F and JAK2 M929I double mutation demonstrated resistance to Jakafi (Ruxolitinib) in culture (PMID: 21926964).	21926964
JAK2 V617F JAK2 R938L	hematologic cancer	resistant	Ruxolitinib	Preclinical	Actionable	In a preclinical study, immune cells expressing the JAK2 V617F and JAK2 R938L double mutation demonstrated resistance to Jakafi (Ruxolitinib) in culture (PMID: 21926964).	21926964
JAK2 V617F JAK2 R938L	hematologic cancer	resistant	Momelotinib	Preclinical	Actionable	In a preclinical study, immune cells expressing the JAK2 V617F and JAK2 R938L double mutation demonstrated resistance to Momelotinib (CYT387) in culture (PMID: 21926964).	21926964
JAK2 V617F JAK2 R938L	hematologic cancer	resistant	Lestaurtinib	Preclinical	Actionable	In a preclinical study, immune cells expressing the JAK2 V617F and JAK2 R938L double mutation demonstrated resistance to Lestaurtinib (CEP-701) in culture (PMID: 21926964).	21926964
JAK2 V617F JAK2 R938L	hematologic cancer	resistant	AZD1480	Preclinical	Actionable	In a preclinical study, immune cells expressing the JAK2 V617F and JAK2 R938L double mutation demonstrated resistance to AZD1480 in culture (PMID: 21926964).	21926964

Showing 1 to 29 of 29 entries

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