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
N1 - Publisher Copyright:
© 2017 by The American Society of Hematology.
PY - 2017/12/28
Y1 - 2017/12/28
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, primaryMPNcell 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 MPNlike 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.
AB - 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, primaryMPNcell 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 MPNlike 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.
KW - Animals
KW - Calreticulin/genetics
KW - Cell Line
KW - DNA Repair/drug effects
KW - Drug Synergism
KW - Heterografts
KW - Humans
KW - Janus Kinase 2/genetics
KW - Mice
KW - Myeloproliferative Disorders/drug therapy
KW - Neoplasms/drug therapy
KW - Nitriles
KW - Phthalazines/pharmacology
KW - Piperazines/pharmacology
KW - Poly(ADP-ribose) Polymerase Inhibitors/pharmacology
KW - Pyrazoles/pharmacology
KW - Pyrimidines
KW - Receptors, Thrombopoietin/genetics
KW - Tumor Cells, Cultured
UR - http://www.scopus.com/inward/record.url?scp=85039801281&partnerID=8YFLogxK
U2 - 10.1182/blood-2017-05-784942
DO - 10.1182/blood-2017-05-784942
M3 - Article
C2 - 29042365
SN - 0006-4971
VL - 130
SP - 2848
EP - 2859
JO - Blood
JF - Blood
IS - 26
ER -