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Ref Type Journal Article
PMID (30730307)
Authors Stivala S, Codilupi T, Brkic S, Baerenwaldt A, Ghosh N, Hao-Shen H, Dirnhofer S, Dettmer MS, Simillion C, Kaufmann BA, Chiu S, Keller M, Kleppe M, Hilpert M, Buser AS, Passweg JR, Radimerski T, Skoda RC, Levine RL, Meyer SC
Title Targeting compensatory MEK/ERK activation increases JAK inhibitor efficacy in myeloproliferative neoplasms.
Abstract Text Constitutive JAK2 signaling is central to myeloproliferative neoplasm (MPN) pathogenesis and results in activation of STAT, PI3K/AKT, and MEK/ERK signaling. However, the therapeutic efficacy of current JAK2 inhibitors is limited. We investigated the role of MEK/ERK signaling in MPN cell survival in the setting of JAK inhibition. Type I and II JAK2 inhibition suppressed MEK/ERK activation in MPN cell lines in vitro, but not in Jak2V617F and MPLW515L mouse models in vivo. JAK2 inhibition ex vivo inhibited MEK/ERK signaling, suggesting that cell-extrinsic factors maintain ERK activation in vivo. We identified PDGFRα as an activated kinase that remains activated upon JAK2 inhibition in vivo, and PDGF-AA/PDGF-BB production persisted in the setting of JAK inhibition. PDGF-BB maintained ERK activation in the presence of ruxolitinib, consistent with its function as a ligand-induced bypass for ERK activation. Combined JAK/MEK inhibition suppressed MEK/ERK activation in Jak2V617F and MPLW515L mice with increased efficacy and reversal of fibrosis to an extent not seen with JAK inhibitors. This demonstrates that compensatory ERK activation limits the efficacy of JAK2 inhibition and dual JAK/MEK inhibition provides an opportunity for improved therapeutic efficacy in MPNs and in other malignancies driven by aberrant JAK-STAT signaling.


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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
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
JAK2 V617F polycythemia vera sensitive Binimetinib + CHZ868 Preclinical Actionable In a preclinical study, CHZ868 and Mektovi (binimetinib) combination treatment decreased splenomegaly, reticulocytes, hematocrit, and allele burden, and reduced expansion of progenitor cells, an effect not observed with treatment of either agent alone, in a mouse model of polycythemia vera harboring JAK2 V617F (PMID: 30730307). 30730307
JAK2 V617F myelofibrosis sensitive Binimetinib + Ruxolitinib Preclinical - Patient cell culture Actionable In a preclinical study, Jakafi (ruxolitinib) and Mektovi (binimetinib) combination treatment resulted in enhanced inhibition of colony growth in bone marrow and peripheral blood mononuclear cells (PBMCs) derived from myelofibrosis patients harboring JAK2 V617F in culture compared to Jakafi (ruxolitinib) alone (PMID: 30730307). 30730307
JAK2 V617F polycythemia vera sensitive Binimetinib + Ruxolitinib Preclinical Actionable In a preclinical study, Jakafi (ruxolitinib) and Mektovi (binimetinib) combination treatment resulted in increased inhibition of Erk phosphorylation and signaling, decreased splenomegaly, hematocrit, and reticulocytes, and decreased bone marrow fibrosis in a mouse model of polycythemia vera harboring JAK2 V617F compared to either drug alone (PMID: 30730307). 30730307