Tony R Green, Katarzyna Piwocka, Huaqing Zhao, Silvia Maifrede, Elizaveta A Belyaeva, Martin Kirschner, Steffen Koschmieder, Morgan Nawrocki, Yashodhara Dasgupta, Josef T Prchal, Lucia Kubovcakova, Martyna Solecka, Margaret Nieborowska-Skorska, Mariusz Wasik, Alison R Moliterno, Bac Viet Le, Katherine Sullivan, Tomasz Skorski, Sylwia Flis, Radek C Skoda
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.