Parp Inhibitors Are Effective In Idh1/2 Mutant Mds And Aml Resistant To Targeted Idh Inhibitors

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are heterogeneous clonal disorders. Isocitrate dehydrogenase-1 and -2 (IDH1/2) mutations are detected in ~20% of AML and ~5% of MDS, in which they confer gain of a neomorphic function that leads to the production of (R)-2-hydroxyglutarate (2HG). Targeted inhibition of mutant IDH1/2 has resulted in significant responses in IDH1/2 mutant MDS and AML but is not curative and patients relapse (Stein et al. Blood 2016, DiNardo et al. N Engl J Med 2018). 2HG accumulation inhibits the function of histone demethylases (KDM4A and KDM4B) that are critical for the homologous recombination (HR) DNA repair pathway and consequently for the repair of DNA double strand breaks (DSBs) (Mallette et al. EMBO J 2012, Sulkowski et al. Sci Transl Med 2017). In HR deficient tumors, Poly-ADP-Ribose Polymerase (PARP) is essential for DNA single strand break (SSB) repair. In IDH mutant tumors PARP inhibitors induce synthetic lethality by suppressing the repair of SSBs, which eventually get converted into DSBs (Javle and Curtin Br J Cancer 2011). We previously demonstrated that in AML, IDH1/2 mutations impair DNA damage response by inducing a defect in HR, and that this renders leukemia cells susceptible to PARP inhibitors in vitro. We hypothesized that this vulnerability would also exist in IDH mutant MDS and more importantly, that this vulnerability would persist in MDS/AML resistant to IDH1/2 inhibitors.