Reversing regulatory safeguards: Targeting the ATR pathway to overcome PARP inhibitor resistance

The development of poly (ADP-ribose) polymerase inhibitors (PARPis) is widely considered a therapeutic milestone in the management of BRCA1/2-deficient malignancies. Since a growing number of cancer treatment guidelines include PARPis, the inevitably emerging PARPi resistance becomes a serious limitation that must be addressed. Targeting the DNA damage response signaling kinase, ATR (ataxia telangiectasia and rad3-related serine/threonine kinase), activated in response to PARPi-induced replication stress, represents a promising approach in fighting PARPi-resistant cancers. The success of this combination therapy in preclinical models has inspired efforts to translate its potential through extensive clinical research and clinical trials. However, the available clinical evidence suggests that PARPi/ATRi combinations have yet to reach their anticipated therapeutic potential. In this review, we summarize work elucidating mechanisms underpinning the effectiveness of ATRi in fighting PARPi resistance and review translational studies reporting efficacy in different types of cancer. Finally, we discuss potential biomarkers of patient selection for customized combinations of PARPi/ATRi treatments.