Abstract
Poly (ADP-ribose) polymerases (PARPs) play an important role in various cellular processes, such as replication, recombination, chromatin remodeling, and DNA repair. Emphasizing PARP’s role in facilitating DNA repair, the PARP pathway has been a target for cancer researchers in developing compounds which selectively target cancer cells and increase sensitivity of cancer cells to other anticancer agents, but which also leave normal cells unaffected. Since certain tumors (BRCA1/2 mutants) have deficient homologous recombination repair pathways, they depend on PARP-mediated base excision repair for survival. Thus, inhibition of PARP is a promising strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. Although PARP inhibitor therapy has predominantly targeted BRCA-mutated cancers, this review also highlights the growing conversation around PARP inhibitor treatment for non-BRCA-mutant tumors, those which exhibit BRCAness and homologous recombination deficiency. We provide an update on the field’s progress by considering PARP inhibitor mechanisms, predictive biomarkers, and clinical trials of PARP inhibitors in development. Bringing light to these findings would provide a basis for expanding the use of PARP inhibitors beyond BRCA-mutant breast tumors.
Highlights
Breast cancer is among the three most common cancers worldwide
Poly (ADP-ribose) polymerases (PARPs) inhibition is a promising therapeutic strategy to treat breast cancer, PARP inhibitors have clinical activity restricted to a small category of patients with BRCA mutations
The challenge is to determine the differences in breast cancer cell line responsiveness to PARP inhibition
Summary
Breast cancer is among the three most common cancers worldwide. It is consistently the leading cause of disability-adjusted life-years (DALYs) and the leading cause of death in women [1]. HR-positive breast cancers, which initially responded well to hormone therapy, can develop into recurrent tumors with downregulation or loss of ER or PR, a finding which may contribute to resistance to endocrine therapy and highlights the challenges associated with breast cancer treatment [4,5,6]. BRCA mutation status is one phenomenon being studied for developing targeted therapies against TNBC and other breast cancer subtypes. Over 80% of breast cancer patients with a BRCA1 mutation have TNBC [8]. Published clinical studies suggest that germline BRCA mutation-associated (gBRCAm) breast cancers are more sensitive to DNA-damaging therapies like poly (adenosine diphosphate ribose) polymerase (PARP) inhibitors [9]. With the field of PARP inhibitor therapy rapidly advancing, PARPi warrant further clinical evaluation for treating the heterogeneous nature of breast cancer subtypes. We discuss the resistance mechanisms emerging against PARPi
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