1. Ruxolitinib-induced defects in DNA repair cause sensitivity to PARP inhibitors in myeloproliferative neoplasms
- Author
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Martin Kirschner, Josef T. Prchal, Bac Viet Le, Tomasz Skorski, Katherine J. Sullivan, Mariusz A. Wasik, Martyna Solecka, Elizaveta A. Belyaeva, Steffen Koschmieder, Lucia Kubovcakova, Yashodhara Dasgupta, Alison R. Moliterno, Radek C. Skoda, Sylwia Flis, Morgan Nawrocki, Margaret Nieborowska-Skorska, Katarzyna Piwocka, Tony Green, Huaqing Zhao, Silvia Maifrede, Green, Tony [0000-0002-9795-0218], and Apollo - University of Cambridge Repository
- Subjects
0301 basic medicine ,Ruxolitinib ,DNA Repair ,DNA repair ,Poly ADP ribose polymerase ,Immunology ,Synthetic lethality ,Poly(ADP-ribose) Polymerase Inhibitors ,Biochemistry ,Poly (ADP-Ribose) Polymerase Inhibitor ,Piperazines ,Olaparib ,Cell Line ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Myeloproliferative Disorders ,hemic and lymphatic diseases ,Neoplasms ,Nitriles ,medicine ,Tumor Cells, Cultured ,Animals ,Humans ,Genetics ,biology ,Chemistry ,food and beverages ,Drug Synergism ,Cell Biology ,Hematology ,Janus Kinase 2 ,3. Good health ,030104 developmental biology ,Pyrimidines ,Cancer research ,biology.protein ,Heterografts ,Phthalazines ,Pyrazoles ,Calreticulin ,Receptors, Thrombopoietin ,medicine.drug - 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.
- Published
- 2017