Abstract
Simple SummaryTwo to three percent of breast cancer patients harbor germline mutation of either BRCA1 or BRCA2 genes. Their tumor cells are deficient in homologous recombination, a BRCA-dependent DNA repair machinery. These deficient cells survive thanks to the PARP-mediated alternative pathway. Therefore, PARP inhibitors have already shown some level of efficiency in the treatment of metastatic breast cancer patients. Unfortunately, some tumor cells inevitably resist PARP inhibitors by different mechanisms. In this review, we (i) present the notion of homologous recombination deficiency and its evaluation methods, (ii) detail the PARP inhibitor clinical trials in breast cancer, (iii) briefly describe the mechanisms to PARP inhibitors resistance, and (iv) discuss some strategies currently under evaluation to enhance the therapeutic index of PARP inhibitors in breast cancer.As poly-(ADP)-ribose polymerase (PARP) inhibition is synthetic lethal with the deficiency of DNA double-strand (DSB) break repair by homologous recombination (HR), PARP inhibitors (PARPi) are currently used to treat breast cancers with mutated BRCA1/2 HR factors. Unfortunately, the increasingly high rate of PARPi resistance in clinical practice has dented initial hopes. Multiple resistance mechanisms and acquired vulnerabilities revealed in vitro might explain this setback. We describe the mechanisms and vulnerabilities involved, including newly identified modes of regulation of DSB repair that are now being tested in large cohorts of patients and discuss how they could lead to novel treatment strategies to improve the therapeutic index of PARPi.
Highlights
The poly(ADP-ribose) polymerases, PARP1 and PARP2, are known to transduce DNA damage signals through their high-affinity with single-stranded DNA breaks (SSBs)
Chromatin decompaction and loading of repair factors in response to ssDNA breaks is facilitated by the action of poly-(ADP)-ribose polymerase (PARP) proteins and the recruitment of PAR-binding effector proteins
The PAR-binding chromatin remodeler ALC1, which was recently identified as an actor of PARP inhibitors (PARPi) toxicity in homologous recombination (HR)-deficient cells through the accumulation of PARP trapping and stalled replication forks [102], is a novel potential therapeutic target in HR-deficient breast cancers
Summary
The poly(ADP-ribose) polymerases, PARP1 and PARP2, are known to transduce DNA damage signals through their high-affinity with single-stranded DNA breaks (SSBs) This is achieved by the activation of histone PARylation followed by chromatin decompaction and the loading of DNA repair factors. PARP inhibitors (PARPi) are toxic in homologous recombination (HR)-deficient cells, notably in breast cancer (BC) cells mutated in HR genes BRCA. This is due to the trapping effect of the PARP enzymes on chromatin leading to a restricted accessibility to the repair factors and to the accumulation of lesions that generate replication-coupled double-stranded DNA breaks (DSBs)/single-stranded DNA (ss DNA)-gaps, which need homology-directed repair by BRCA1/2 and RAD51. We list the causes of HRD and briefly discuss methods for diagnosing HRD
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