Preclinical Investigation of Inhibition of the DNA Damage Response as a Targetted Therapy in Myeloproliferative Neoplasms Shows Synergism of ATR Inhibitors with Standard-of-Care Treatment

Myeloproliferative neoplasms (MPNs) are a group of haematological malignancies arising from haematopoietic stem cells (HSCs) with acquired driver mutations in JAK2, MPL and CALR. Current therapies are not selective for the mutant HSC population. Increased replication stress is seen in the presence of mutant JAK2, suggesting DNA damage response inhibitors (DDRi) may differentially affect mutant HSCs over wild-type HSCs to restore normal haematopoiesis. Using JAK2V617F and CALR (del 52) mutant cell lines, we observed that ATR inhibition (ATRi) by AZD6738 and VE-821 significantly reduced viability. The combination of ATRi and a hydroxyurea/a JAK1/2 inhibitor—ruxolitinib—demonstrated high synergism in both apoptosis induction and proliferation arrest. This study provides preliminary evidence that ATRi combined with standard therapies may be exploited in MPNs harbouring JAK2 and CALR mutations.