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Blood ; 130(26): 2848-2859, 2017 12 28.
Artículo en Inglés | MEDLINE | ID: mdl-29042365

RESUMEN

Myeloproliferative neoplasms (MPNs) often carry JAK2(V617F), MPL(W515L), or CALR(del52) mutations. Current treatment options for MPNs include cytoreduction by hydroxyurea and JAK1/2 inhibition by ruxolitinib, both of which are not curative. We show here that cell lines expressing JAK2(V617F), MPL(W515L), or CALR(del52) accumulated reactive oxygen species-induced DNA double-strand breaks (DSBs) and were modestly sensitive to poly-ADP-ribose polymerase (PARP) inhibitors olaparib and BMN673. At the same time, primary MPN cell samples from individual patients displayed a high degree of variability in sensitivity to these drugs. Ruxolitinib inhibited 2 major DSB repair mechanisms, BRCA-mediated homologous recombination and DNA-dependent protein kinase-mediated nonhomologous end-joining, and, when combined with olaparib, caused abundant accumulation of toxic DSBs resulting in enhanced elimination of MPN primary cells, including the disease-initiating cells from the majority of patients. Moreover, the combination of BMN673, ruxolitinib, and hydroxyurea was highly effective in vivo against JAK2(V617F)+ murine MPN-like disease and also against JAK2(V617F)+, CALR(del52)+, and MPL(W515L)+ primary MPN xenografts. In conclusion, we postulate that ruxolitinib-induced deficiencies in DSB repair pathways sensitized MPN cells to synthetic lethality triggered by PARP inhibitors.


Asunto(s)
Reparación del ADN/efectos de los fármacos , Trastornos Mieloproliferativos/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Pirazoles/farmacología , Animales , Calreticulina/genética , Línea Celular , Sinergismo Farmacológico , Xenoinjertos , Humanos , Janus Quinasa 2/genética , Ratones , Trastornos Mieloproliferativos/genética , Neoplasias/genética , Nitrilos , Ftalazinas/farmacología , Piperazinas/farmacología , Pirimidinas , Receptores de Trombopoyetina/genética , Células Tumorales Cultivadas
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