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Ruxolitinib-induced defects in DNA repair cause sensitivity to PARP inhibitors in myeloproliferative neoplasms.

Accepted version
Peer-reviewed

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Authors

Nieborowska-Skorska, Margaret 
Maifrede, Silvia 
Dasgupta, Yashodhara 
Sullivan, Katherine 
Flis, Sylwia 

Abstract

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.

Description

Keywords

Animals, Calreticulin, Cell Line, DNA Repair, Drug Synergism, Heterografts, Humans, Janus Kinase 2, Mice, Myeloproliferative Disorders, Neoplasms, Nitriles, Phthalazines, Piperazines, Poly(ADP-ribose) Polymerase Inhibitors, Pyrazoles, Pyrimidines, Receptors, Thrombopoietin, Tumor Cells, Cultured

Journal Title

Blood

Conference Name

Journal ISSN

0006-4971
1528-0020

Volume Title

130

Publisher

American Society of Hematology
Sponsorship
Medical Research Council (MC_PC_12009)
Cancer Research UK (21762)