Synthetic lethality of decitabine plus ATR inhibition for TP53-mutated AML

TP53 mutations are found in 10% to 15% of myeloid neoplasms and are associated with a dismal prognosis. Although hypomethylating agents (HMAs), such as decitabine, are active in TP53-mutated myeloid neoplasms (TP53-MN), mutation clearance is rarely complete and nearly all patients relapse. Molecular determinants of response to HMAs in TP53-MN are poorly understood. Here, we show that decitabine induces replicative stress with decreased replication fork progression, induction of single-strand DNA breaks, and activation of the ataxia telangiectasia mutated–Rad3-related (ATR) pathway. Resolution of decitabine-induced replication stress is impaired in TP53-mutated acute myeloid leukemia (AML) cells, representing a potential therapeutic vulnerability. Indeed, the combination of decitabine and ATR inhibition (ATRi) induces synthetic lethality that is selective for TP53-AML and due, in part, to induction of mitotic catastrophe. Interestingly, this synergistic lethality was not observed with azacitidine or treatment with GSK3685032, a potent DNA methyltransferase 1 inhibitor, both of which produce a comparable level of global hypomethylation to decitabine. Treatment with decitabine and an ATR inhibitor reduces leukemia burden and prolongs survival in in vivo mouse models of TP53-mutated AML. Collectively, these findings show that TP53 loss generates a selective vulnerability to decitabine-induced replication stress, with the combination of ATRi and decitabine showing promise as a new therapeutic approach for TP53-MN.