Due to its potent cytotoxicity in BRCA-mutated tumors, synthetic lethality elicited by poly (ADP-ribose) polymerase (PARP) inhibitor gives renewed enthusiasm to researching and developing anti-cancer therapies. Chronic myeloid leukemia (CML) is a type of cancers that starts in certain blood-forming cells of the bone marrow. Here, we showed that poly (ADP-ribose) polymerase (PARP) inhibitor talazoparib could induce a concentration-dependent cytotoxicity in CML cells derived from pediatric patients. During talazoparib treatment, autophagy was markedly activated, which was confirmed by the accumulation of autophagosomes, decrease of SQSTM1 and up-regulation of LC3-II. Inhibition of autophagy by pharmaceutical inhibitor chloroquine or small-interfering RNA siATG5 significantly increased the cytotoxicity of talazoparib in pediatric CML cells and elicited synergistic anti-tumor effect in patient-derived xenograft model. Our data demonstrated that autophagy played a cyto-protective role in talazoparib-treated pediatric CML and co-treatment with talazoparib and autophagy inhibitor could induce synergetic anti-tumor effect, providing novel insights for pediatric CML treatment.
Keywords: Autophagy; Cytotoxicity; Pediatric chronic myeloid leukemia; Talazoparib.