DUSP6 mediates resistance to JAK2 inhibition and drives leukemic progression

Kong, Tim; Laranjeira, Angelo Brunelli Albertoni; Yang, Kangning; Fisher, Daniel A.C.; Yu, LaYow; Frégonnière, Laure Poittevin De La; Wang, Anthony Z.; Ruzinova, Marianna B.; Fowles, Jared S.; Fulbright, Mary; Cox, Maggie J; Celik, Hamza; Challen, Grant A.; Huang, Sidong; Oh, Stephen T.

doi:10.1038/s43018-022-00486-8

Cited by 13 publications

(16 citation statements)

References 73 publications

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“…Non‐FLT3 targeting JAK2 inhibitors ruxolitinib and itacitinib demonstrated lower potency. These results in addition to our previous report 18 that CD34+ HSPCs from sAML patients exhibit elevated wild‐type FLT3 expression suggest that inhibitors with the capacity to simultaneously target FLT3 and JAK–STAT could prove to be beneficial across leukemias with distinct underlying genomic alterations.…”

Section: Resultssupporting

confidence: 75%

“…Signaling and cytokine CyTOF experiments utilizing HEL cells and patient PBMCs and BMMCs were conducted on a CyTOF2 mass cytometer (Fluidigm) with validated antibody panels following protocol as previously described. 18,25,26,45 In brief, cells were labeled with cisplatin, washed, and incubated with indicated stimulant or inhibitor for the indicated duration. Cells were then fixed with paraformaldehyde, permeabilized, and barcoded.…”

Section: Suspension Mass Cytometry (Cytof)mentioning

confidence: 99%

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Comprehensive profiling of clinical JAK inhibitors in myeloproliferative neoplasms

Kong

Laranjeira

et al. 2023

American J Hematol

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Small molecule inhibitors targeting JAK2 provide symptomatic benefits for myeloproliferative neoplasm (MPN) patients and are among first‐line therapeutic agents. However, despite all having potent capacity to suppress JAK–STAT signaling, they demonstrate distinct clinical profiles suggesting contributory effects in targeting other ancillary pathways. Here, we performed comprehensive profiling on four JAK2 inhibitors either FDA‐approved (ruxolitinib, fedratinib, and pacritinib) or undergoing phase 3 studies (momelotinib) to better outline mechanistic and therapeutic efficacy. Across JAK2‐mutant in vitro models, all four inhibitors demonstrated similar anti‐proliferative phenotypes, whereas pacritinib yielded greatest potency on suppressing colony formation in primary samples, while momelotinib exhibited unique erythroid colony formation sparing. All inhibitors reduced leukemic engraftment, disease burden, and extended survival across patient‐derived xenograft (PDX) models, with strongest effects elicited by pacritinib. Through RNA‐sequencing and gene set enrichment analyses, differential suppressive degrees of JAK–STAT and inflammatory response signatures were revealed, which we validated with signaling and cytokine suspension mass cytometry across primary samples. Lastly, we assessed the capacity of JAK2 inhibitors to modulate iron regulation, uncovering potent suppression of hepcidin and SMAD signaling by pacritinib. These comparative findings provide insight into the differential and beneficial effects of ancillary targeting beyond JAK2 and may help guide the use of specific inhibitors in personalized therapy.

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Section: Resultssupporting

confidence: 75%

Section: Suspension Mass Cytometry (Cytof)mentioning

confidence: 99%

Comprehensive profiling of clinical JAK inhibitors in myeloproliferative neoplasms

Kong

Laranjeira

et al. 2023

American J Hematol

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“…17,18,21 Notably, downstream targets and regulators of MAPK signaling, DUSP1 and DUSP6, have recently been shown to play a role in JAK2 inhibitor persistence and progression of disease. 22,23 The SHP2 (Src homology region 2 domain-containing phosphatase-2) tyrosine phosphatase mediates RAS activation and subsequent MEK/ERK signaling downstream of cytokine receptors and receptor tyrosine kinases by relieving negative regulatory phosphorylation events on various proteins that normally antagonize RAS activation. 24,25 Activating mutations in SHP2 (encoded by PTPN11) are drivers of certain leukemias (e.g., JMML) demonstrating the ability of SHP2 signaling to contribute to hematopoietic neoplasms.…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, MEK and ERK inhibition have been shown to antagonize MPN phenotypes in mice and improve responses to ruxolitinib therapy including, importantly, antagonizing mutant allele burden levels 17,18,21 . Notably, downstream targets and regulators of MAPK signaling, DUSP1 and DUSP6, have recently been shown to play a role in JAK2 inhibitor persistence and progression of disease 22,23 …”

Section: Introductionmentioning

confidence: 99%

SHP2 inhibition displays efficacy as a monotherapy and in combination with JAK2 inhibition in preclinical models of myeloproliferative neoplasms

Pandey,

Mazzacurati,

Rowsell

et al. 2024

American J Hematol

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Myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocytosis, and primary myelofibrosis, are clonal hematopoietic neoplasms driven by mutationally activated signaling by the JAK2 tyrosine kinase. Although JAK2 inhibitors can improve MPN patients' quality of life, they do not induce complete remission as disease‐driving cells persistently survive therapy. ERK activation has been highlighted as contributing to JAK2 inhibitor persistent cell survival. As ERK is a component of signaling by activated RAS proteins and by JAK2 activation, we sought to inhibit RAS activation to enhance responses to JAK2 inhibition in preclinical MPN models. We found the SHP2 inhibitor RMC‐4550 significantly enhanced growth inhibition of MPN cell lines in combination with the JAK2 inhibitor ruxolitinib, effectively preventing ruxolitinib persistent growth, and the growth and viability of established ruxolitinib persistent cells remained sensitive to SHP2 inhibition. Both SHP2 and JAK2 inhibition diminished cellular RAS‐GTP levels, and their concomitant inhibition enhanced ERK inactivation and increased apoptosis. Inhibition of SHP2 inhibited the neoplastic growth of MPN patient hematopoietic progenitor cells and exhibited synergy with ruxolitinib. RMC‐4550 antagonized MPN phenotypes and increased survival of an MPN mouse model driven by MPL‐W515L. The combination of RMC‐4550 and ruxolitinib, which was safe and tolerated in healthy mice, further inhibited disease compared to ruxolitinib monotherapy, including extending survival. Given SHP2 inhibitors are undergoing clinical evaluation in patients with solid tumors, our preclinical findings suggest that SHP2 is a candidate therapeutic target with potential for rapid translation to clinical assessment to improve current targeted therapies for MPN patients.

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“… 3 Furthermore, aberrant NFκB signaling mediates a pro-inflammatory microenvironment that contributes to disease progression and transformation in MPN. 4 – 7 …”

mentioning

confidence: 99%

A phase I trial of pevonedistat in combination with ruxolitinib for the treatment of myelofibrosis

Kong,

Gaudin,

Gordon

et al. 2024

Therapeutic Advances in Hematology

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Janus kinase 2 (JAK2) inhibitors such as ruxolitinib have become standard-of-care therapy for patients with myeloproliferative neoplasms (MPNs); however, activation of alternate oncogenic pathways including nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) has limited durable response as single-agent therapy. With the rationale of targeting both pathways, we conducted a phase I dose escalation trial of pevonedistat in combination with ruxolitinib for the treatment of patients with myelofibrosis (NCT03386214). The primary objective was to assess the safety and tolerability of combination therapy with additional objectives of treatment efficacy and alterations of biomarkers. There were no dose-limiting toxicities observed with most adverse events being limited to grades 1/2. In secondary measures, anemia response was observed in two patients. Pro-inflammatory cytokines and iron parameters were longitudinally assessed, which revealed suppression of interleukin-6 and interferon-gamma in a dose-dependent manner across a subset of patients. These results suggest that combination therapy targeting both JAK2 and NFκB may hold clinical merit for MPN patients.

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DUSP6 mediates resistance to JAK2 inhibition and drives leukemic progression

Cited by 13 publications

References 73 publications

Comprehensive profiling of clinical JAK inhibitors in myeloproliferative neoplasms

Comprehensive profiling of clinical JAK inhibitors in myeloproliferative neoplasms

SHP2 inhibition displays efficacy as a monotherapy and in combination with JAK2 inhibition in preclinical models of myeloproliferative neoplasms

A phase I trial of pevonedistat in combination with ruxolitinib for the treatment of myelofibrosis

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