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The PIM inhibitor AZD1208 synergizes with ruxolitinib to induce apoptosis of ruxolitinib sensitive and resistant JAK2-V617F-driven cells and inhibit colony formation of primary MPN cells.
Oncotarget 2015; 6(37):40141-57O

Abstract

Classical myeloproliferative neoplasms (MPNs) are hematopoietic stem cell disorders that exhibit excess mature myeloid cells, bone marrow fibrosis, and risk of leukemic transformation. Aberrant JAK2 signaling plays an etiological role in MPN formation. Because neoplastic cells in patients are largely insensitive to current anti-JAK2 therapies, effective therapies remain needed. Members of the PIM family of serine/threonine kinases are induced by JAK/STAT signaling, regulate hematopoietic stem cell growth, protect hematopoietic cells from apoptosis, and exhibit hematopoietic cell transforming properties. We hypothesized that PIM kinases may offer a therapeutic target for MPNs. We treated JAK2-V617F-dependent MPN model cells as well as primary MPN patient cells with the PIM kinase inhibitors SGI-1776 and AZD1208 and the JAK2 inhibitor ruxolitinib. While MPN model cells were rather insensitive to PIM inhibitors, combination of PIM inhibitors with ruxolitinib led to a synergistic effect on MPN cell growth due to enhanced apoptosis. Importantly, PIM inhibitor mono-therapy inhibited, and AZD1208/ruxolitinib combination therapy synergistically suppressed, colony formation of primary MPN cells. Enhanced apoptosis by combination therapy was associated with activation of BAD, inhibition of downstream components of the mTOR pathway, including p70S6K and S6 protein, and activation of 4EBP1. Importantly, PIM inhibitors re-sensitized ruxolitinib-resistant MPN cells to ruxolitinib by inducing apoptosis. Finally, exogenous expression of PIM1 induced ruxolitinib resistance in MPN model cells. These data indicate that PIMs may play a role in MPNs and that combining PIM and JAK2 kinase inhibitors may offer a more efficacious therapeutic approach for MPNs over JAK2 inhibitor mono-therapy.

Authors+Show Affiliations

Department of Molecular Oncology, Moffitt Cancer Center, Tampa, FL, USA.Department of Molecular Oncology, Moffitt Cancer Center, Tampa, FL, USA.Department of Molecular Oncology, Moffitt Cancer Center, Tampa, FL, USA.Department of Molecular Oncology, Moffitt Cancer Center, Tampa, FL, USA.Department of Molecular Oncology, Moffitt Cancer Center, Tampa, FL, USA. Oncology iMed, AstraZeneca, Waltham, MA, USA.Department of Molecular Oncology, Moffitt Cancer Center, Tampa, FL, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26472029

Citation

Mazzacurati, Lucia, et al. "The PIM Inhibitor AZD1208 Synergizes With Ruxolitinib to Induce Apoptosis of Ruxolitinib Sensitive and Resistant JAK2-V617F-driven Cells and Inhibit Colony Formation of Primary MPN Cells." Oncotarget, vol. 6, no. 37, 2015, pp. 40141-57.
Mazzacurati L, Lambert QT, Pradhan A, et al. The PIM inhibitor AZD1208 synergizes with ruxolitinib to induce apoptosis of ruxolitinib sensitive and resistant JAK2-V617F-driven cells and inhibit colony formation of primary MPN cells. Oncotarget. 2015;6(37):40141-57.
Mazzacurati, L., Lambert, Q. T., Pradhan, A., Griner, L. N., Huszar, D., & Reuther, G. W. (2015). The PIM inhibitor AZD1208 synergizes with ruxolitinib to induce apoptosis of ruxolitinib sensitive and resistant JAK2-V617F-driven cells and inhibit colony formation of primary MPN cells. Oncotarget, 6(37), pp. 40141-57. doi:10.18632/oncotarget.5653.
Mazzacurati L, et al. The PIM Inhibitor AZD1208 Synergizes With Ruxolitinib to Induce Apoptosis of Ruxolitinib Sensitive and Resistant JAK2-V617F-driven Cells and Inhibit Colony Formation of Primary MPN Cells. Oncotarget. 2015 Nov 24;6(37):40141-57. PubMed PMID: 26472029.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The PIM inhibitor AZD1208 synergizes with ruxolitinib to induce apoptosis of ruxolitinib sensitive and resistant JAK2-V617F-driven cells and inhibit colony formation of primary MPN cells. AU - Mazzacurati,Lucia, AU - Lambert,Que T, AU - Pradhan,Anuradha, AU - Griner,Lori N, AU - Huszar,Dennis, AU - Reuther,Gary W, PY - 2015/07/06/received PY - 2015/09/30/accepted PY - 2015/10/17/entrez PY - 2015/10/17/pubmed PY - 2016/9/22/medline KW - JAK2-V617F KW - MPN KW - PIM KW - kinase inhibitor KW - therapy SP - 40141 EP - 57 JF - Oncotarget JO - Oncotarget VL - 6 IS - 37 N2 - Classical myeloproliferative neoplasms (MPNs) are hematopoietic stem cell disorders that exhibit excess mature myeloid cells, bone marrow fibrosis, and risk of leukemic transformation. Aberrant JAK2 signaling plays an etiological role in MPN formation. Because neoplastic cells in patients are largely insensitive to current anti-JAK2 therapies, effective therapies remain needed. Members of the PIM family of serine/threonine kinases are induced by JAK/STAT signaling, regulate hematopoietic stem cell growth, protect hematopoietic cells from apoptosis, and exhibit hematopoietic cell transforming properties. We hypothesized that PIM kinases may offer a therapeutic target for MPNs. We treated JAK2-V617F-dependent MPN model cells as well as primary MPN patient cells with the PIM kinase inhibitors SGI-1776 and AZD1208 and the JAK2 inhibitor ruxolitinib. While MPN model cells were rather insensitive to PIM inhibitors, combination of PIM inhibitors with ruxolitinib led to a synergistic effect on MPN cell growth due to enhanced apoptosis. Importantly, PIM inhibitor mono-therapy inhibited, and AZD1208/ruxolitinib combination therapy synergistically suppressed, colony formation of primary MPN cells. Enhanced apoptosis by combination therapy was associated with activation of BAD, inhibition of downstream components of the mTOR pathway, including p70S6K and S6 protein, and activation of 4EBP1. Importantly, PIM inhibitors re-sensitized ruxolitinib-resistant MPN cells to ruxolitinib by inducing apoptosis. Finally, exogenous expression of PIM1 induced ruxolitinib resistance in MPN model cells. These data indicate that PIMs may play a role in MPNs and that combining PIM and JAK2 kinase inhibitors may offer a more efficacious therapeutic approach for MPNs over JAK2 inhibitor mono-therapy. SN - 1949-2553 UR - https://www.unboundmedicine.com/medline/citation/26472029/The_PIM_inhibitor_AZD1208_synergizes_with_ruxolitinib_to_induce_apoptosis_of_ruxolitinib_sensitive_and_resistant_JAK2_V617F_driven_cells_and_inhibit_colony_formation_of_primary_MPN_cells_ L2 - http://www.impactjournals.com/oncotarget/misc/linkedout.php?pii=5653 DB - PRIME DP - Unbound Medicine ER -