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Ruxolitinib-induced defects in DNA repair cause sensitivity to PARP inhibitors in myeloproliferative neoplasms.
Blood 2017; 130(26):2848-2859Blood

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.

Authors+Show Affiliations

Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA.Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA.Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA.Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA.Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA. Department of Pharmacology, National Medicines Institute, Warsaw, Poland.Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA. Laboratory of Cytometry, Nencki Institute of Experimental Biology, Warsaw, Poland.Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA.Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA.Department of Biomedicine, University Hospital Basel/University of Basel, Basel, Switzerland.Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA.Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany.Department of Clinical Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA.School of Medicine, University of Utah, Salt Lake City, UT.Laboratory of Cytometry, Nencki Institute of Experimental Biology, Warsaw, Poland.Division of Hematology, Department of Medicine, School of Medicine, The Johns Hopkins University, Baltimore, MD; and.Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA.Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany.Cambridge Institute for Medical Research. Wellcome-Medical Research Council Cambridge Stem Cell Institute, and. Department of Haematology, University of Cambridge, Cambridge, United Kingdom; and.Department of Biomedicine, University Hospital Basel/University of Basel, Basel, Switzerland.Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA. Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29042365

Citation

Nieborowska-Skorska, Margaret, et al. "Ruxolitinib-induced Defects in DNA Repair Cause Sensitivity to PARP Inhibitors in Myeloproliferative Neoplasms." Blood, vol. 130, no. 26, 2017, pp. 2848-2859.
Nieborowska-Skorska M, Maifrede S, Dasgupta Y, et al. Ruxolitinib-induced defects in DNA repair cause sensitivity to PARP inhibitors in myeloproliferative neoplasms. Blood. 2017;130(26):2848-2859.
Nieborowska-Skorska, M., Maifrede, S., Dasgupta, Y., Sullivan, K., Flis, S., Le, B. V., ... Skorski, T. (2017). Ruxolitinib-induced defects in DNA repair cause sensitivity to PARP inhibitors in myeloproliferative neoplasms. Blood, 130(26), pp. 2848-2859. doi:10.1182/blood-2017-05-784942.
Nieborowska-Skorska M, et al. Ruxolitinib-induced Defects in DNA Repair Cause Sensitivity to PARP Inhibitors in Myeloproliferative Neoplasms. Blood. 2017 12 28;130(26):2848-2859. PubMed PMID: 29042365.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Ruxolitinib-induced defects in DNA repair cause sensitivity to PARP inhibitors in myeloproliferative neoplasms. AU - Nieborowska-Skorska,Margaret, AU - Maifrede,Silvia, AU - Dasgupta,Yashodhara, AU - Sullivan,Katherine, AU - Flis,Sylwia, AU - Le,Bac Viet, AU - Solecka,Martyna, AU - Belyaeva,Elizaveta A, AU - Kubovcakova,Lucia, AU - Nawrocki,Morgan, AU - Kirschner,Martin, AU - Zhao,Huaqing, AU - Prchal,Josef T, AU - Piwocka,Katarzyna, AU - Moliterno,Alison R, AU - Wasik,Mariusz, AU - Koschmieder,Steffen, AU - Green,Tony R, AU - Skoda,Radek C, AU - Skorski,Tomasz, Y1 - 2017/10/17/ PY - 2017/05/12/received PY - 2017/10/12/accepted PY - 2017/10/19/pubmed PY - 2018/1/25/medline PY - 2017/10/19/entrez SP - 2848 EP - 2859 JF - Blood JO - Blood VL - 130 IS - 26 N2 - 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. SN - 1528-0020 UR - https://www.unboundmedicine.com/medline/citation/29042365/Ruxolitinib_induced_defects_in_DNA_repair_cause_sensitivity_to_PARP_inhibitors_in_myeloproliferative_neoplasms_ L2 - http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=29042365 DB - PRIME DP - Unbound Medicine ER -