Targeting the BRCA1/2 deficient cancer with PARP inhibitors: Clinical outcomes and mechanistic insights

Abstract

BRCA1 and BRCA2 play a critical role in a variety of molecular processes related to DNA metabolism, including homologous recombination and mediating the replication stress response. Individuals with mutations in the BRCA1 and BRCA2 (BRCA1/2) genes have a significantly higher risk of developing various types of cancers, especially cancers of the breast, ovary, pancreas, and prostate. Currently, the Food and Drug Administration (FDA) has approved four PARP inhibitors (PARPi) to treat cancers with BRCA1/2 mutations. In this review, we will first summarize the clinical outcomes of the four FDA-approved PARPi in treating BRCA1/2 deficient cancers. We will then discuss evidence supporting the hypothesis that the cytotoxic effect of PARPi is likely due to inducing excessive replication stress at the difficult-to-replicate (DTR) genomic regions in BRCA1/2 mutated tumors. Finally, we will discuss the ongoing preclinical and clinical studies on how to combine the PARPi with immuno-oncology drugs to further improve clinical outcomes.

The potential of PCNA inhibition as a therapeutic strategy in cervical cancer

“…This has been leveraged to better treat breast cancers that cannot complete the pathway due to mutations in the BRCA1 or BRCA2. 50 Consistent with the ideas that HPV-induced changes in DNA repair can be targeted therapeutically and that HPV oncogenes impair the homologous recombination pathway, recurrent CaCx has been successful treated using Olaparib. 51 The induction of replication stress by HPV E7 is another example of where the changes needed to facilitate the viral life cycle are important for the treatment of cancers caused by HPV.…”

“…The inability to repair DSBs using the homologous recombination pathway makes cells sensitive to a category of drugs known as PARP inhibitors (e.g., Olaparib). This has been leveraged to better treat breast cancers that cannot complete the pathway due to mutations in the BRCA1 or BRCA2 50 . Consistent with the ideas that HPV‐induced changes in DNA repair can be targeted therapeutically and that HPV oncogenes impair the homologous recombination pathway, recurrent CaCx has been successful treated using Olaparib 51 …”

Protein-Folding Chaperones Predict Structure-Function Relationships and Cancer Risk inBRCA1Mutation Carriers

“…Tumor suppressor BRCA1 is essential to life 38 . BRCA1 inactivation by mutation increases the lifetime risk of developing breast and ovarian cancers by up to 7-8-fold in women 39 and strongly predisposes individuals to pancreatic and prostate cancers 6,40 . The tumor suppressive role of BRCA1 is attributable to the ability of the encoded BRCA1 protein to prevent a central hallmark of cancer, genome instability.…”

Special Issue “DNA Replication/Repair, and the DNA Damage Response in Human Disease”

“…Mutations of numerous genes involved in DNA replication, DNA repair, and DNA damage response (DDR) pathways lead to a variety of human diseases, including aging and cancer [ 1 ]. With the approval of PARP inhibitors in treating certain cancers carrying mutations in the BRCA1 and/or BRCA2 genes [ 2 ], targeting the DNA metabolism has become an important strategy in drug discovery. This Special Issue of Genes highlights the critical components of DNA replication, DNA repair, and DDR, as well as their potential roles in human diseases.…”

“…Therefore, these are called translesion synthesis (TLS) DNA polymerases. In a review article, Eckert discusses the non-canonical functions of DNA polymerase η, with an emphasis on its role in facilitating DNA synthesis through the difficult-to-replicate genomic regions, including telomeres, common fragile sites (CFS), centromeres, rDNA loci [ 2 , 6 ], and the potential roles for its reverse-transcriptase activity [ 7 ]. In addition to its canonical function in synthesizing the lagging strands, DNA polymerase δ is also an essential component of a unique homology-dependent repair (HDR) pathway, called break-induced replication (BIR) [ 8 , 9 ].…”