Reference Detail

Ref Type

Journal Article

PMID

(33782031)

Authors

Rampal RK, Pinzon-Ortiz M, Somasundara AVH, Durham B, Koche R, Spitzer B, Mowla S, Krishnan A, Li B, An W, Derkach A, Devlin S, Rong X, Longmire T, Eisman SE, Cordner K, Whitfield JT, Vanasse G, Cao ZA, Levine RL

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	27	12	2021 Jun 15	3456-3468	Clin Cancer Res

URL

Abstract Text

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

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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

Gene	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	leukemia	predicted - sensitive	LGH447 + Ribociclib + Ruxolitinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, combination treatment with Jakafi (ruxolitinib), LGH447, and Kisqali (ribociclib) led to complete tumor regression in a cell line xenograft model of leukemia harboring JAK2 V617F (PMID: 33782031).	33782031
JAK2 V617F	myeloproliferative neoplasm	sensitive	LGH447 + Ribociclib + Ruxolitinib	Preclinical	Actionable	In a preclinical study, combination treatment with Jakafi (ruxolitinib), LGH447, and Kisqali (ribociclib) led to decreased white blood cell and platelet counts, decreased spleen size compared to Jakafi (ruxolitinib) treatment alone, and normocellular bone marrow with appropriate maturation a mouse model of myeloproliferative neoplasm harboring JAK2 V617F (PMID: 33782031).	33782031