The pan-PIM inhibitor INCB053914 displays potent synergy in combination with ruxolitinib in models of MPN.
Animals
Cell Line, Tumor
Cell Proliferation
/ drug effects
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Synergism
Heterografts
Humans
Janus Kinase Inhibitors
/ pharmacology
Mechanistic Target of Rapamycin Complex 1
/ metabolism
Mice
Myeloproliferative Disorders
/ drug therapy
Neoplastic Stem Cells
/ drug effects
Nitriles
Protein Kinase Inhibitors
/ pharmacology
Proto-Oncogene Proteins c-pim-1
/ antagonists & inhibitors
Pyrazoles
/ pharmacology
Pyrimidines
Signal Transduction
/ drug effects
Journal
Blood advances
ISSN: 2473-9537
Titre abrégé: Blood Adv
Pays: United States
ID NLM: 101698425
Informations de publication
Date de publication:
26 11 2019
26 11 2019
Historique:
received:
05
04
2019
accepted:
15
10
2019
entrez:
15
11
2019
pubmed:
15
11
2019
medline:
9
9
2020
Statut:
ppublish
Résumé
Aberrant JAK2 tyrosine kinase signaling drives the development of Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis. However, JAK2 kinase inhibitors have failed to significantly reduce allele burden in MPN patients, underscoring the need for improved therapeutic strategies. Members of the PIM family of serine/threonine kinases promote cellular proliferation by regulating a variety of cellular processes, including protein synthesis and the balance of signaling that regulates apoptosis. Overexpression of PIM family members is oncogenic, exemplified by their ability to induce lymphomas in collaboration with c-Myc. Thus, PIM kinases are potential therapeutic targets for several malignancies such as solid tumors and blood cancers. We and others have shown that PIM inhibitors augment the efficacy of JAK2 inhibitors by using in vitro models of MPNs. Here we report that the recently developed pan-PIM inhibitor INCB053914 augments the efficacy of the US Food and Drug Administration-approved JAK1/2 inhibitor ruxolitinib in both in vitro and in vivo MPN models. INCB053914 synergizes with ruxolitinib to inhibit cell growth in JAK2-driven MPN models and induce apoptosis. Significantly, low nanomolar INCB053914 enhances the efficacy of ruxolitinib to inhibit the neoplastic growth of primary MPN patient cells, and INCB053914 antagonizes ruxolitinib persistent myeloproliferation in vivo. These findings support the notion that INCB053914, which is currently in clinical trials in patients with advanced hematologic malignancies, in combination with ruxolitinib may be effective in MPN patients, and they support the clinical testing of this combination in MPN patients.
Identifiants
pubmed: 31725895
pii: 422778
doi: 10.1182/bloodadvances.2019000260
pmc: PMC6880903
doi:
Substances chimiques
Janus Kinase Inhibitors
0
Nitriles
0
Protein Kinase Inhibitors
0
Pyrazoles
0
Pyrimidines
0
ruxolitinib
82S8X8XX8H
Mechanistic Target of Rapamycin Complex 1
EC 2.7.11.1
Proto-Oncogene Proteins c-pim-1
EC 2.7.11.1
proto-oncogene proteins pim
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3503-3514Subventions
Organisme : CSRD VA
ID : I01 CX000114
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA076292
Pays : United States
Informations de copyright
© 2019 by The American Society of Hematology.
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