Therapeutic Efficacy of Combined JAK1/2, Pan-PIM, and CDK4/6 Inhibition in Myeloproliferative Neoplasms

Clin Cancer Res. 2021 Jun 15;27(12):3456-3468. doi: 10.1158/1078-0432.CCR-20-4898. Epub 2021 Mar 29.


Purpose: The JAK1/2 inhibitor ruxolitinib has demonstrated significant benefits for patients with myeloproliferative neoplasms (MPN). However, patients often lose response to ruxolitinib or suffer disease progression despite therapy with ruxolitinib. These observations have prompted efforts to devise treatment strategies to improve therapeutic efficacy in combination with ruxolitinib therapy. Activation of JAK-STAT signaling results in dysregulation of key downstream pathways, notably increased expression of cell-cycle mediators including CDC25A and the PIM kinases.

Experimental design: Given the involvement of cell-cycle mediators in MPNs, we sought to examine the efficacy of therapy combining ruxolitinib with a CDK4/6 inhibitor (LEE011) and a PIM kinase inhibitor (PIM447). We utilized JAK2-mutant cell lines, murine models, and primary MPN patient samples for these studies.

Results: Exposure of JAK2-mutant cell lines to the triple combination of ruxolitinib, LEE011, and PIM447 resulted in expected on-target pharmacodynamic effects, as well as increased apoptosis and a decrease in the proportion of cells in S-phase, compared with ruxolitinib. As compared with ruxolitinib monotherapy, combination therapy led to reductions in spleen and liver size, reduction of bone marrow reticulin fibrosis, improved overall survival, and elimination of disease-initiating capacity of treated bone marrow, in murine models of MPN. Finally, the triple combination reduced colony formation capacity of primary MPN patient samples to a greater extent than ruxolitinib.

Conclusions: The triple combination of ruxolitinib, LEE011, and PIM447 represents a promising therapeutic strategy with the potential to increase therapeutic responses in patients with MPN.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cyclin-Dependent Kinase 4 / metabolism
  • Cyclin-Dependent Kinase 6
  • Humans
  • Janus Kinase 1
  • Janus Kinase 2 / metabolism
  • Mice
  • Myeloproliferative Disorders* / drug therapy
  • Myeloproliferative Disorders* / genetics
  • Myeloproliferative Disorders* / metabolism
  • Neoplasms*
  • Nitriles / pharmacology
  • Primary Myelofibrosis*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Signal Transduction


  • Nitriles
  • Protein Kinase Inhibitors
  • JAK1 protein, human
  • Jak1 protein, mouse
  • Jak2 protein, mouse
  • Janus Kinase 1
  • Janus Kinase 2
  • CDK4 protein, human
  • Cdk4 protein, mouse
  • Cdk6 protein, mouse
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6