The pan-PIM inhibitor INCB053914 displays potent synergy in combination with ruxolitinib in models of MPN

Mazzacurati, Lucia; Collins, Robert J.; Pandey, Garima; Lambert-Showers, Que T.; Amin, Narmin E.; Zhang, Ling; Stubbs, Matthew C.; Epling-Burnette, Pearlie K.; Koblish, Holly K.; Reuther, Gary W.

doi:10.1182/bloodadvances.2019000260

Cited by 24 publications

(29 citation statements)

References 77 publications

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“…We found strong supra-additivity in cell lines treated with various combined doses of inhibitors, regardless of their sensitivity to PIM inhibition alone. These data demonstrating supra-additivity in HNSCC are consistent with recently demonstrated synergy between PIM inhibitors and PI3K inhibitors in prostate cancer [54], MET inhibitors in lung cancer [55], mTOR inhibitors in leukemia [56] and Janus kinase (JAK) inhibitors in myeloproliferative neoplasms [57,58].…”

Section: Discussionsupporting

confidence: 88%

Human papillomavirus insertions identify the PIM family of serine/threonine kinases as targetable driver genes in head and neck squamous cell carcinoma

Broutian

Jiang

et al. 2020

Cancer Letters

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Human papillomavirus (HPV) insertions in cancer genomes have been linked to various forms of focal genomic instability and altered expression of neighboring genes. Here we tested the hypothesis that investigation of HPV insertions in a head and neck cancer squamous cell carcinoma (HNSCC) cell line would identify targetable driver genes contributing to oncogenesis of other HNSCC. In the cell line UPCI:SCC090, HPV16 integration amplified PIM1 serine/ threonine kinase gene ~16-fold, thereby increasing transcript and protein levels. We used genetic and pharmacological approaches to inhibit PIM kinases in this and other HNSCC cell lines. Knockdown of PIM1 transcripts by transfected short hairpin RNAs reduced UPCI:SCC090 viability. CRISPR/Cas9-mediated mutagenesis of PIM1 caused cell cycle arrest and apoptosis.

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Section: Discussionsupporting

confidence: 88%

Human papillomavirus insertions identify the PIM family of serine/threonine kinases as targetable driver genes in head and neck squamous cell carcinoma

Broutian

Jiang

et al. 2020

Cancer Letters

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Section: Novel Therapies Targeting Mpn Stem Cells Via Signaling mentioning

confidence: 99%

“…PIM kinase is a family of anti-apoptotic serine/threonine proto-oncogenes that are transcriptionally activated by JAK/STAT signalling [ 272 , 284 , 285 , 286 ]. In MPN, continuous activation of JAK/STAT pathway is observed, making PIM kinase a potential therapeutic target [ 272 , 286 ]. Although the efficacy of PIM kinase inhibitor monotherapy is limited [ 285 ], it acts synergistically with ruxolitinib to suppress JAK2 signalling effectively [ 285 , 286 ].…”

Section: Novel Therapies Targeting Mpn Stem Cells Via Signaling mentioning

confidence: 99%

Targeting Abnormal Hematopoietic Stem Cells in Chronic Myeloid Leukemia and Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms

Yung

Lee

Chu

et al. 2021

IJMS

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Myeloproliferative neoplasms (MPNs) are unique hematopoietic stem cell disorders sharing mutations that constitutively activate the signal-transduction pathways involved in haematopoiesis. They are characterized by stem cell-derived clonal myeloproliferation. The key MPNs comprise chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). CML is defined by the presence of the Philadelphia (Ph) chromosome and BCR-ABL1 fusion gene. Despite effective cytoreductive agents and targeted therapy, complete CML/MPN stem cell eradication is rarely achieved. In this review article, we discuss the novel agents and combination therapy that can potentially abnormal hematopoietic stem cells in CML and MPNs and the CML/MPN stem cell-sustaining bone marrow microenvironment.

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“…Given the excessive proliferation of hematopoietic cells in MPN, the PIM-CDK4/6 axis has been proposed as a therapeutic target. 81 PIM inhibition showed synergistic effects with ruxolitinib in preclinical MPN models 82 and triple inhibition of PIM, CDK4/6, and JAK2 is under evaluation in MF. 83 …”

Section: Novel Therapeutic Approaches In Mpn Treatmentmentioning

confidence: 99%

Challenges and Perspectives for Therapeutic Targeting of Myeloproliferative Neoplasms

Brkić

Meyer

2020

HemaSphere

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Myeloproliferative neoplasms (MPNs) are hematopoietic stem cell disorders with dysregulated myeloid blood cell production and propensity for transformation to acute myeloid leukemia, thrombosis, and bleeding. Acquired mutations in JAK2, MPL, and CALR converge on hyperactivation of Janus kinase 2 (JAK2) signaling as a central feature of MPN. Accordingly, JAK2 inhibitors have held promise for therapeutic targeting. After the JAK1/2 inhibitor ruxolitinib, similar JAK2 inhibitors as fedratinib are entering clinical use. While patients benefit with reduced splenomegaly and symptoms, disease-modifying effects on MPN clone size and clonal evolution are modest. Importantly, response to ruxolitinib may be lost upon treatment suggesting the MPN clone acquires resistance. Resistance mutations, as seen with other tyrosine kinase inhibitors, have not been described in MPN patients suggesting that functional processes reactivate JAK2 signaling. Compensatory signaling, which bypasses JAK2 inhibition, and other processes contribute to intrinsic resistance of MPN cells restricting efficacy of JAK2 inhibition overall. Combinations of JAK2 inhibition with pegylated interferon-α, a well-established therapy of MPN, B-cell lymphoma 2 inhibition, and others are in clinical development with the potential to enhance therapeutic efficacy. Novel single-agent approaches targeting other molecules than JAK2 are being investigated clinically. Special focus should be placed on myelofibrosis patients with anemia and thrombocytopenia, a delicate patient population at high need for options. The extending range of new treatment approaches will increase the therapeutic options for MPN patients. This calls for concomitant improvement of our insight into MPN biology to inform tailored therapeutic strategies for individual MPN patients.

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The pan-PIM inhibitor INCB053914 displays potent synergy in combination with ruxolitinib in models of MPN

Abstract: Key Points INCB053914 and ruxolitinib synergize to induce apoptosis of JAK2V617F-driven cells and to inhibit neoplastic growth of primary MPN cells. INCB053914 antagonizes ruxolitinib persistence in an in vivo MPN model.

Cited by 24 publications

References 77 publications

Human papillomavirus insertions identify the PIM family of serine/threonine kinases as targetable driver genes in head and neck squamous cell carcinoma

Human papillomavirus insertions identify the PIM family of serine/threonine kinases as targetable driver genes in head and neck squamous cell carcinoma

Targeting Abnormal Hematopoietic Stem Cells in Chronic Myeloid Leukemia and Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms

Challenges and Perspectives for Therapeutic Targeting of Myeloproliferative Neoplasms

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