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1.
Clin Cancer Res ; 27(12): 3456-3468, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33782031

RESUMO

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.


Assuntos
Transtornos Mieloproliferativos , Neoplasias , Mielofibrose Primária , Animais , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina , Humanos , Janus Quinase 1 , Janus Quinase 2/metabolismo , Camundongos , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/metabolismo , Nitrilas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Transdução de Sinais
2.
Cancer Biomark ; 15(1): 79-87, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25524945

RESUMO

BACKGROUND: The JAK-STAT pathway is an important signaling pathway downstream of multiple cytokine and growth factor receptors. Dysregulated JAK-STAT signaling has been implicated in the pathogenesis of multiple human malignancies. OBJECTIVE: Given this pivotal role of JAK-STAT dysregulation, it is important to identify patients with an overactive JAK-STAT pathway for possible treatment with JAK inhibitors. METHODS: We developed a gene signature assay to detect overactive JAK-STAT signaling. The cancer cell line encyclopedia and associated gene-expression data were used to correlate the activation status of STAT5 with the induction of a set of STAT5 target genes. RESULTS: Four target genes were identified (PIM1, CISH, SOCS2, and ID1), the expression of which correlated significantly with pSTAT5 status in 40 hematologic tumor cell lines. In pSTAT5-positive models, the expression of the gene signature genes decreased following ruxolitinib treatment, which corresponded to pSTAT5 downmodulation. In pSTAT5-negative cell lines, neither pSTAT5 modulation nor a change in signature gene expression was observed following ruxolitinib treatment. CONCLUSIONS: The gene signature can potentially be used to stratify or enrich for patient populations with activated JAK-STAT5 signaling that might benefit from treatments targeting JAK-STAT signaling. Furthermore, the 4-gene signature is a predictor of the pharmacodynamic effects of ruxolitinib.


Assuntos
Neoplasias Hematológicas/genética , Neoplasias Hematológicas/metabolismo , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismo , Animais , Linhagem Celular Tumoral , Feminino , Neoplasias Hematológicas/tratamento farmacológico , Xenoenxertos , Humanos , Janus Quinases/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Nitrilas , Pirazóis/farmacologia , Pirimidinas , Transdução de Sinais/efeitos dos fármacos
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