Reference Detail

Ref Type Journal Article
PMID (26472029)
Authors Mazzacurati L, Lambert QT, Pradhan A, Griner LN, Huszar D, Reuther GW
Title 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.
Journal Oncotarget
Vol 6
Issue 37
Date 2015 Nov 24
URL
Abstract Text 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.

Filtering

  • Case insensitive filtering will display rows where any text in any cell matches the filter term
  • Simple literal full or partial string matches
  • Separate multiple filter terms with a spaces, order doesn't matter (a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page, filtering has no impact on query parameters
  • Use quotes to match a longer phrase which contains spaces "mtor c1483f"

Sorting

  • Generally, the default sort order for tables is set to be first column ascending, however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column, be sure to set ascending or descending order for a given column, before moving on to the next column.

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
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 bone marrow cancer decreased response AZD1208 Preclinical Actionable In a preclinical study, myeloproliferative cancer cell lines harboring JAK2 V617F demonstrated reduced sensitivity to AZD1208 induced growth inhibition in culture (PMID: 26472029). 26472029
JAK2 V617F bone marrow cancer sensitive AZD1208 + Ruxolitinib Preclinical Actionable In a preclinical study, Jakafi (ruxolitinib) worked synergistically with AZD1208 to inhibit proliferation of myeloproliferative cancer cell lines harboring JAK2 V617F in culture (PMID: 26472029). 26472029
JAK2 V617F bone marrow cancer sensitive Ruxolitinib + SGI-1776 Preclinical Actionable In a preclinical study, Jakafi (ruxolitinib) worked synergistically with SGI-1776 to inhibit proliferation of myeloproliferative cancer cell lines harboring JAK2 V617F in culture (PMID: 26472029). 26472029
Unknown unknown T-cell leukemia no benefit AZD1208 + Ruxolitinib Preclinical Actionable In a preclinical study, Jakafi (ruxolitinib) and AZD1208 combination treatment did not inhibit proliferation of a T-cell leukemia cell line in culture (PMID: 26472029). 26472029
JAK2 V617F bone marrow cancer decreased response SGI-1776 Preclinical Actionable In a preclinical study, myeloproliferative cancer cell lines harboring JAK2 V617F demonstrated reduced sensitivity to SGI-1776 induced growth inhibition in culture (PMID: 26472029). 26472029