Palbociclib, a drug approved to treat HR-positive and HER2-negative breast cancer, could lead to improvement in symptoms of myelofibrosis when combined with the JAK2 inhibitor ruxolitinib, according to results from murine models published in Cancer Research.
“The JAK2 inhibitors ruxolitinib and fedratinib have been approved for treatment of myelofibrosis, but they do not offer significant improvement of bone marrow fibrosis,” the authors, led by Avik Dutta, PhD, explained. Based on research demonstrating that CDK6 expression is significantly elevated in MPN/myelofibrosis hematopoietic progenitor cells, Dr. Dutta and colleagues evaluated the efficacy of the CDK4/6 inhibitor palbociclib alone or in combination with ruxolitinib in Jak2V617F and MPLW515L murine models of myelofibrosis.
When models were treated with palbociclib alone, leukocytosis and splenomegaly were significantly reduced. Bone marrow fibrosis also was inhibited, the researchers added.
Similarly, the combination of palbociclib and ruxolitinib resulted in normalization of peripheral blood leukocyte counts, marked reduction of spleen size, and abrogation of bone marrow fibrosis in murine models of myelofibrosis.
Palbociclib treatment also preferentially inhibited Jak2V617F mutant hematopoietic progenitors in mice. “Mechanistically, treatment with palbociclib or depletion of CDK6 inhibited Aurora kinase, NF-κB, and TGFβ signaling pathways in Jak2V617F mutant hematopoietic cells and attenuated expression of fibrotic markers in the bone marrow,” the authors added.
“Overall, these data suggest that palbociclib in combination with ruxolitinib may have therapeutic potential for treatment of myelofibrosis and support the clinical investigation of this drug combination in patients with myelofibrosis,” they concluded.