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Nieborowska-Skorska M , Maifrede S , Dasgupta Y , Sullivan K , Flis S , Le BV , Solecka M , Belyaeva EA , Kubovcakova L , Nawrocki M , Kirschner M , Zhao H , Prchal JT , Piwocka K , Moliterno AR , Wasik M , Koschmieder S , Green TR , Skoda RC , Skorski T
Ruxolitinib-induced defects in DNA repair cause sensitivity to PARP inhibitors in myeloproliferative neoplasms
Blood. 2017 Dec 28;130(26) :2848-2859
PMID: 29042365    PMCID: PMC5746670    URL: https://www.ncbi.nlm.nih.gov/pubmed/29042365
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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 the sensitivity to these drugs. Ruxolitinib inhibited two major DSB repair mechanisms, BRCA-mediated homologous recombination and DNA-PK -mediated non-homologous 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)-positive murine MPN-like disease and also against JAK2(V617F), CALR(del52), and MPL(W515L)-positive 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.
Notes
1528-0020 Nieborowska-Skorska, Margaret Maifrede, Silvia Dasgupta, Yashodhara Sullivan, Katherine Flis, Sylwia Le, Bac Viet Solecka, Martyna Belyaeva, Elizaveta A Kubovcakova, Lucia Nawrocki, Morgan Kirschner, Martin Zhao, Huaqing Prchal, Josef T Piwocka, Katarzyna Moliterno, Alison R Wasik, Mariusz Koschmieder, Steffen Green, Tony R Skoda, Radek C Skorski, Tomasz Journal Article United States Blood. 2017 Oct 17. pii: blood-2017-05-784942. doi: 10.1182/blood-2017-05-784942.