PARP Inhibitors in Breast and Ovarian Cancer

Abstract

Poly (ADP-ribose) polymerase (PARP) inhibitors are one of the most successful examples of clinical translation of targeted therapies in medical oncology, and this has been demonstrated by their effective management of BRCA1/BRCA2 mutant cancers, most notably in breast and ovarian cancers. PARP inhibitors target DNA repair pathways that BRCA1/2-mutant tumours are dependent upon. Inhibition of the key components of these pathways leads to DNA damage triggering subsequent critical levels of genomic instability, mitotic catastrophe and cell death. This ultimately results in a synthetic lethal relationship between BRCA1/2 and PARP, which underpins the effectiveness of PARP inhibitors. Despite the early and dramatic response seen with PARP inhibitors, patients receiving them often develop treatment resistance. To date, data from both clinical and preclinical studies have highlighted multiple resistance mechanisms to PARP inhibitors, and only by understanding these mechanisms are we able to overcome the challenges. The focus of this review is to summarise the underlying mechanisms underpinning treatment resistance to PARP inhibitors and to aid both clinicians and scientists to develop better clinically applicable assays to better select patients who would derive the greatest benefit as well as develop new novel/combination treatment strategies to overcome these mechanisms of resistance. With a better understanding of PARP inhibitor resistance mechanisms, we would not only be able to identify a subset of patients who are unlikely to benefit from therapy but also to sequence our treatment paradigm to avoid and overcome these resistance mechanisms.

FSP1 inhibition enhances olaparib sensitivity in BRCA-proficient ovarian cancer patients via a nonferroptosis mechanism

“…The most studied mechanisms of acquired PARPi resistance include the restoration of HR activity due to reverse mutations in HR genes, the stabilization of replication forks induced by other DNA repair factors and the reduction in the effective intracellular dose of PARPis due to the increased rate of PARPi removal [ 6 , 8 , 35 ]. However, the cause of primary drug resistance has not been elucidated.…”

Exploration of poly (ADP‐ribose) polymerase inhibitor resistance in the treatment of BRCA1/2‐mutated cancer

“…This kind of misrepair often causes DNA sequence alterations around DSB sites. This accumulation of erroneously repaired DSBs over a long period of time causes genomic instability, leading to cell death 44,45 …”

Discovery of Tetrahydropyrazolopyrazine Derivatives as Potent and Selective MYT1 Inhibitors for the Treatment of Cancer

“…Breast and gynecological cancers are major threats to women’s health, fertility, and overall quality of life. , The clinical approval of poly­(ADP-ribose) polymerase (PARP) inhibitors has significantly improved the prognosis for patients with BRCA1/2 mutations; however, most patients lack these mutations, and resistance to PARP inhibitors is commonly observed . To discover novel treatment options for patients with breast cancer and gynecological cancers, we used PandaOmics, an AI-powered platform, to identify new therapeutic targets in ovarian, endometrial, cervical, and breast cancer, particularly triple-negative breast cancer.…”