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Ref Type Journal Article
PMID (39091915)
Authors Gorantla SP, Prince G, Osius J, Dinesh DC, Boddu V, Duyster J, von Bubnoff N
Title Type II mode of JAK2 inhibition and destabilization are potential therapeutic approaches against the ruxolitinib resistance driven myeloproliferative neoplasms.
Journal Vol Issue Date Pages Journal Short Title
Frontiers in oncology 14 2024 1430833 Front Oncol
URL
Abstract Text Ruxolitinib has been approved by the US FDA for the treatment of myeloproliferative neoplasms such as polycythemia vera and primary myelofibrosis. Ruxolitinib will remain a main stay in the treatment of MPN patients due to its effective therapeutic benefits. However, there have been instances of ruxolitinib resistance in MPN patients. As JAK2 is a direct target of ruxolitinib, we generated ruxolitinib-resistant clones to find out the mechanism of resistance.Cell-based screening strategy was used to detect the ruxolitinib-resistant mutations in JAK2. The Sanger sequencing method was used to detect the point mutations in JAK2. Mutations were re-introduced using the site-directed mutagenesis method and stably expressed in Ba/F3 cells. Drug sensitivities against the JAK2 inhibitors were measured using an MTS-based assay. JAK2 and STAT5 activation levels and total proteins were measured using immunoblotting. Computational docking studies were performed using the Glide module of Schrodinger Maestro software.In this study, we have recovered seven residues in the kinase domain of JAK2 that affect ruxolitinib sensitivity. All these mutations confer cross-resistance across the panel of JAK2 kinase inhibitors except JAK2-L983F. JAK2-L983F reduces the sensitivity towards ruxolitinib. However, it is sensitive towards fedratinib indicating that our screen identifies the drug-specific resistance profiles. All the ruxolitinib-resistant JAK2 variants displayed sensitivity towards type II JAK2 inhibitor CHZ-868. In this study, we also found that JAK1-L1010F (homologous JAK2-L983F) is highly resistant towards ruxolitinib suggesting the possibility of JAK1 escape mutations in JAK2-driven MPNs and JAK1 mutated ALL. Finally, our study also shows that HSP90 inhibitors are potent against ruxolitinib-resistant variants through the JAK2 degradation and provides the rationale for clinical evaluation of potent HSP90 inhibitors in genetic resistance driven by JAK2 inhibitors.Our study identifies JAK1 and JAK2 resistance variants against the type I JAK2 inhibitors ruxolitinib, fedratinib, and lestaurtinib. The sensitivity of these resistant variants towards the type II JAK2 inhibitor CHZ-868 indicates that this mode of type II JAK2 inhibition is a potential therapeutic approach against ruxolitinib refractory leukemia. This also proposes the development of potent and specific type II JAK2 inhibitors using ruxolitinib-resistance variants as a prototype.

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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
JAK1 L1010F missense unknown JAK1 L1010F lies within protein kinase domain 2 of the Jak1 protein (UniProt.org). L1010F has been associated with resistance to Jak inhibitors in culture (PMID: 39091915), but has not been fully biochemically characterized and therefore, its effect on Jak1 protein function is unknown. Y
JAK1 L929Q missense unknown JAK1 L929Q lies within protein kinase domain 2 of the Jak1 protein (UniProt.org). L929Q has been associated with resistance to Jak inhibitors in combination with JAK1 V658F in culture (PMID: 39091915), but has not been fully biochemically characterized and therefore, its effect on Jak1 protein function is unknown (PubMed, Sep 2024). Y
JAK2 E1028K missense unknown JAK2 E1028K lies within protein kinase domain 2 of the Jak2 protein (UniProt.org). E1028K is transforming in combination with JAK2 V617F in culture (PMID: 39091915), but has not been individually characterized and therefore, its effect on Jak2 protein function is unknown.
JAK2 L902Q missense unknown JAK2 L902Q lies within protein kinase domain 2 of the Jak2 protein (UniProt.org). L902Q does not result in cytokine-independent growth and is associated with resistance to Jak2 inhibitors in the context of JAK2 V617F in culture (PMID: 39091915), but has not been fully biochemically characterized and therefore, its effect on Jak2 protein function is unknown. Y
JAK2 L983F missense unknown JAK2 L983F lies within the active site of the Jak2 protein (PMID: 26419724). L983F confers resistance to some Jak inhibitors, results in decreased cell proliferation in combination with JAK2 V617F in culture (PMID: 26419724), and is not transforming in culture (PMID: 39091915), but has not been fully biochemically characterized and therefore, its effect on Jak2 protein function is unknown.
JAK2 Q959H missense unknown JAK2 Q959H lies within protein kinase domain 2 of the Jak2 protein (UniProt.org). Q959H is transforming in combination with JAK2 V617F in culture (PMID: 39091915), but has not been individually characterized and therefore, its effect on Jak2 protein function is unknown.
JAK2 R938E missense unknown JAK2 R938E lies within protein kinase domain 2 of the Jak2 protein (UniProt.org). R938E is transforming in combination with JAK2 V617F in culture (PMID: 39091915), but has not been individually characterized and therefore, its effect on Jak2 protein function is unknown.
JAK2 R947Q missense unknown JAK2 R947Q lies within protein kinase domain 2 of the Jak2 protein (UniProt.org). R947Q is transforming in combination with JAK2 V617F in culture (PMID: 39091915), but has not been individually characterized and therefore, its effect on Jak2 protein function is unknown.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
JAK1 V658F JAK1 L1010F hematologic cancer resistant Ruxolitinib Preclinical - Cell culture Actionable In a preclinical study, a cell line expressing JAK1 V658F and L1010F was resistant to Jakafi (ruxolitinib) in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 L983F hematologic cancer resistant Ruxolitinib Preclinical - Cell culture Actionable In a preclinical study, a cell line expressing JAK2 V617F and L983F was resistant to Jakafi (ruxolitinib) in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 L902Q hematologic cancer sensitive Geldanamycin Preclinical - Cell culture Actionable In a preclinical study, Geldanamycin inhibited Stat5 signaling and proliferation in a cell line expressing JAK2 V617F and L902Q in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 L902Q hematologic cancer resistant Lestaurtinib Preclinical - Cell culture Actionable In a preclinical study, a cell line expressing JAK2 V617F and L902Q was resistant to Lestaurtinib (CEP-701) in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 Q959H hematologic cancer sensitive Lestaurtinib Preclinical - Cell culture Actionable In a preclinical study, Lestaurtinib (CEP-701) inhibited proliferation of a cell line expressing JAK2 V617F and Q959H in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 Q959H JAK2 L983F hematologic cancer resistant Ruxolitinib Preclinical - Cell culture Actionable In a preclinical study, a cell line expressing JAK2 V617F, L983F, and Q959H was resistant to Jakafi (ruxolitinib) in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 L902Q hematologic cancer sensitive CHZ868 Preclinical - Cell culture Actionable In a preclinical study, CHZ868 inhibited Stat5 signaling and proliferation in a cell line expressing JAK2 V617F and L902Q in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 L983F hematologic cancer sensitive Tanespimycin Preclinical - Cell culture Actionable In a preclinical study, Tanespimycin (17-AAG) inhibited Stat5 signaling and proliferation in a cell line expressing JAK2 V617F and L983F in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 L902Q hematologic cancer sensitive Tanespimycin Preclinical - Cell culture Actionable In a preclinical study, Tanespimycin (17-AAG) inhibited Stat5 signaling and proliferation in a cell line expressing JAK2 V617F and L902Q in culture (PMID: 39091915). 39091915
JAK2 V617F hematologic cancer sensitive Ruxolitinib Preclinical - Cell culture Actionable In a preclinical study, Jakafi (ruxolitinib) inhibited Stat5 signaling and proliferation in a cell line expressing JAK2 V617F in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 L983F hematologic cancer sensitive Lestaurtinib Preclinical - Cell culture Actionable In a preclinical study, Lestaurtinib (CEP-701) inhibited proliferation of a cell line expressing JAK2 V617F and L983F in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 L902Q JAK2 E1028K hematologic cancer resistant Fedratinib Preclinical - Cell culture Actionable In a preclinical study, a cell line expressing JAK2 V617F, L902Q, and E1028K was resistant to Inrebic (fedratinib) in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 Y931C hematologic cancer sensitive Geldanamycin Preclinical - Cell culture Actionable In a preclinical study, Geldanamycin inhibited Stat5 signaling and proliferation in a cell line expressing JAK2 V617F and Y931C in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 L902Q JAK2 E1028K hematologic cancer sensitive Geldanamycin Preclinical - Cell culture Actionable In a preclinical study, Geldanamycin inhibited Stat5 signaling and proliferation in a cell line expressing JAK2 V617F, L902Q, and E1028K in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 L902Q JAK2 R938E hematologic cancer resistant Fedratinib Preclinical - Cell culture Actionable In a preclinical study, a cell line expressing JAK2 V617F, L902Q, and R938E was resistant to Inrebic (fedratinib) in culture (PMID: 39091915). 39091915
JAK2 V617F hematologic cancer sensitive Lestaurtinib Preclinical - Cell culture Actionable In a preclinical study, Lestaurtinib (CEP-701) inhibited Stat5 signaling and proliferation in a cell line expressing JAK2 V617F in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 L902Q JAK2 R947Q hematologic cancer resistant Fedratinib Preclinical - Cell culture Actionable In a preclinical study, a cell line expressing JAK2 V617F, L902Q, and R947Q was resistant to Inrebic (fedratinib) in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 L902Q JAK2 E1028K hematologic cancer resistant Ruxolitinib Preclinical - Cell culture Actionable In a preclinical study, a cell line expressing JAK2 V617F, L902Q, and E1028K was resistant to Jakafi (ruxolitinib) in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 L983F hematologic cancer sensitive Fedratinib Preclinical - Cell culture Actionable In a preclinical study, Inrebic (fedratinib) inhibited Stat5 signaling and proliferation in a cell line expressing JAK2 V617F and L983F in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 L902Q JAK2 R938E hematologic cancer resistant Ruxolitinib Preclinical - Cell culture Actionable In a preclinical study, a cell line expressing JAK2 V617F, L902Q, and R938E was resistant to Jakafi (ruxolitinib) in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 Q959H hematologic cancer sensitive Ruxolitinib Preclinical - Cell culture Actionable In a preclinical study, Jakafi (ruxolitinib) inhibited proliferation of a cell line expressing JAK2 V617F and Q959H in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 L902Q hematologic cancer resistant Ruxolitinib Preclinical - Cell culture Actionable In a preclinical study, a cell line expressing JAK2 V617F and L902Q was resistant to Jakafi (ruxolitinib) in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 Y931C hematologic cancer resistant Lestaurtinib Preclinical - Cell culture Actionable In a preclinical study, a cell line expressing JAK2 V617F and Y931C was resistant to Lestaurtinib (CEP-701) in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 Q959H JAK2 L983F hematologic cancer sensitive Tanespimycin Preclinical - Cell culture Actionable In a preclinical study, Tanespimycin (17-AAG) inhibited Stat5 signaling and proliferation in a cell line expressing JAK2 V617F, L983F, and Q959H in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 L902Q JAK2 R938E hematologic cancer sensitive Geldanamycin Preclinical - Cell culture Actionable In a preclinical study, Geldanamycin inhibited Stat5 signaling and proliferation in a cell line expressing JAK2 V617F, L902Q, and R938E in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 R947Q hematologic cancer sensitive Ruxolitinib Preclinical - Cell culture Actionable In a preclinical study, Jakafi (ruxolitinib) inhibited proliferation of a cell line expressing JAK2 V617F and R947Q in culture (PMID: 39091915). 39091915
JAK1 V658F hematologic cancer sensitive Ruxolitinib Preclinical - Cell culture Actionable In a preclinical study, Jakafi (ruxolitinib) inhibited proliferation of a cell line expressing JAK1 V658F in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 R947Q hematologic cancer sensitive Fedratinib Preclinical - Cell culture Actionable In a preclinical study, Inrebic (fedratinib) inhibited proliferation of a cell line expressing JAK2 V617F and R947Q in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 R947Q hematologic cancer sensitive Lestaurtinib Preclinical - Cell culture Actionable In a preclinical study, Lestaurtinib (CEP-701) inhibited proliferation of a cell line expressing JAK2 V617F and R947Q in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 Q959H JAK2 L983F hematologic cancer sensitive Fedratinib Preclinical - Cell culture Actionable In a preclinical study, Inrebic (fedratinib) inhibited Stat5 signaling and proliferation in a cell line expressing JAK2 V617F, L983F, and Q959H in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 E1028K hematologic cancer sensitive Lestaurtinib Preclinical - Cell culture Actionable In a preclinical study, Lestaurtinib (CEP-701) inhibited proliferation of a cell line expressing JAK2 V617F and E1028K in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 Q959H JAK2 L983F hematologic cancer sensitive Lestaurtinib Preclinical - Cell culture Actionable In a preclinical study, Lestaurtinib (CEP-701) inhibited proliferation of a cell line expressing JAK2 V617F, L983F, and Q959H in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 L902Q JAK2 R947Q hematologic cancer resistant Ruxolitinib Preclinical - Cell culture Actionable In a preclinical study, a cell line expressing JAK2 V617F, L902Q, and R947Q was resistant to Jakafi (ruxolitinib) in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 L902Q JAK2 E1028K hematologic cancer resistant Lestaurtinib Preclinical - Cell culture Actionable In a preclinical study, a cell line expressing JAK2 V617F, L902Q, and E1028K was resistant to Lestaurtinib (CEP-701) in culture (PMID: 39091915). 39091915
JAK2 V617F hematologic cancer sensitive Geldanamycin Preclinical - Cell culture Actionable In a preclinical study, Geldanamycin inhibited Stat5 signaling and proliferation in a cell line expressing JAK2 V617F in culture (PMID: 39091915). 39091915
JAK2 V617F hematologic cancer sensitive Tanespimycin Preclinical - Cell culture Actionable In a preclinical study, Tanespimycin (17-AAG) inhibited Stat5 signaling and proliferation in a cell line expressing JAK2 V617F in culture (PMID: 39091915). 39091915
JAK1 V658F JAK1 L929Q hematologic cancer predicted - resistant Ruxolitinib Preclinical - Cell culture Actionable In a preclinical study, a cell line expressing JAK1 V658F and L929Q was moderately resistant to Jakafi (ruxolitinib) in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 L902Q JAK2 R947Q hematologic cancer resistant Lestaurtinib Preclinical - Cell culture Actionable In a preclinical study, a cell line expressing JAK2 V617F, L902Q, and R947Q was resistant to Lestaurtinib (CEP-701) in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 E1028K hematologic cancer sensitive Fedratinib Preclinical - Cell culture Actionable In a preclinical study, Inrebic (fedratinib) inhibited proliferation of a cell line expressing JAK2 V617F and E1028K in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 E1028K hematologic cancer sensitive Ruxolitinib Preclinical - Cell culture Actionable In a preclinical study, Jakafi (ruxolitinib) inhibited proliferation of a cell line expressing JAK2 V617F and E1028K in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 L902Q JAK2 R947Q hematologic cancer sensitive Tanespimycin Preclinical - Cell culture Actionable In a preclinical study, Tanespimycin (17-AAG) inhibited Stat5 signaling and proliferation in a cell line expressing JAK2 V617F, L902Q, and R947Q in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 L983F hematologic cancer sensitive CHZ868 Preclinical - Cell culture Actionable In a preclinical study, CHZ868 inhibited Stat5 signaling and proliferation in a cell line expressing JAK2 V617F and L983F in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 L902Q JAK2 R947Q hematologic cancer sensitive Geldanamycin Preclinical - Cell culture Actionable In a preclinical study, Geldanamycin inhibited Stat5 signaling and proliferation in a cell line expressing JAK2 V617F, L902Q, and R947Q in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 R938E hematologic cancer sensitive Fedratinib Preclinical - Cell culture Actionable In a preclinical study, Inrebic (fedratinib) inhibited proliferation of a cell line expressing JAK2 V617F and R938E in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 L902Q JAK2 R938E hematologic cancer sensitive Tanespimycin Preclinical - Cell culture Actionable In a preclinical study, Tanespimycin (17-AAG) inhibited Stat5 signaling and proliferation in a cell line expressing JAK2 V617F, L902Q, and R938E in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 Y931C hematologic cancer resistant Fedratinib Preclinical - Cell culture Actionable In a preclinical study, Inrebic (fedratinib) inhibited Stat5 signaling and proliferation in a cell line expressing JAK2 V617F and Y931C in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 Q959H hematologic cancer sensitive Fedratinib Preclinical - Cell culture Actionable In a preclinical study, Inrebic (fedratinib) inhibited proliferation of a cell line expressing JAK2 V617F and Q959H in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 L902Q JAK2 E1028K hematologic cancer sensitive Tanespimycin Preclinical - Cell culture Actionable In a preclinical study, Tanespimycin (17-AAG) inhibited Stat5 signaling and proliferation in a cell line expressing JAK2 V617F, L902Q, and E1028K in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 L902Q JAK2 R938E hematologic cancer resistant Lestaurtinib Preclinical - Cell culture Actionable In a preclinical study, a cell line expressing JAK2 V617F, L902Q, and R938E was resistant to Lestaurtinib (CEP-701) in culture (PMID: 39091915). 39091915
JAK2 V617F hematologic cancer sensitive Fedratinib Preclinical - Cell culture Actionable In a preclinical study, Inrebic (fedratinib) inhibited Stat5 signaling and proliferation in a cell line expressing JAK2 V617F in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 Y931C hematologic cancer decreased response CHZ868 Preclinical - Cell culture Actionable In a preclinical study, a cell line expressing JAK2 V617F and Y931C was less sensitive to CHZ868 treatment than cells expressing JAK2 V617F alone in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 Q959H JAK2 L983F hematologic cancer sensitive Geldanamycin Preclinical - Cell culture Actionable In a preclinical study, Geldanamycin inhibited Stat5 signaling and proliferation in a cell line expressing JAK2 V617F, L983F, and Q959H in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 L983F hematologic cancer sensitive Geldanamycin Preclinical - Cell culture Actionable In a preclinical study, Geldanamycin inhibited Stat5 signaling and proliferation in a cell line expressing JAK2 V617F and L983F in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 Y931C hematologic cancer sensitive Tanespimycin Preclinical - Cell culture Actionable In a preclinical study, Tanespimycin (17-AAG) inhibited Stat5 signaling and proliferation in a cell line expressing JAK2 V617F and Y931C in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 L902Q hematologic cancer resistant Fedratinib Preclinical - Cell culture Actionable In a preclinical study, a cell line expressing JAK2 V617F and L902Q was resistant to Inrebic (fedratinib) in culture (PMID: 39091915). 39091915
JAK2 V617F hematologic cancer sensitive CHZ868 Preclinical - Cell culture Actionable In a preclinical study, CHZ868 inhibited Stat5 signaling and proliferation in a cell line expressing JAK2 V617F in culture (PMID: 39091915). 39091915
JAK2 V617F JAK2 Y931C hematologic cancer resistant Ruxolitinib Preclinical - Cell culture Actionable In a preclinical study, a cell line expressing JAK2 V617F and Y931C was resistant to Jakafi (ruxolitinib) in culture (PMID: 39091915). 39091915