作者
Nirashaa T Bound, Cassandra J Vandenberg, Apriliana ER Kartikasari, Magdalena Plebanski, Clare L Scott
发表日期
2022/9/9
来源
Frontiers in Genetics
卷号
13
页码范围
886170
出版商
Frontiers Media SA
简介
High-grade serous ovarian carcinoma (HGSOC) is a genomically unstable malignancy responsible for over 70% of all deaths due to ovarian cancer. With roughly 50% of all HGSOC harboring defects in the homologous recombination (HR) DNA repair pathway (e.g., BRCA1/2 mutations), the introduction of poly ADP-ribose polymerase inhibitors (PARPi) has dramatically improved outcomes for women with HR defective HGSOC. By blocking the repair of single-stranded DNA damage in cancer cells already lacking high-fidelity HR pathways, PARPi causes the accumulation of double-stranded DNA breaks, leading to cell death. Thus, this synthetic lethality results in PARPi selectively targeting cancer cells, resulting in impressive efficacy. Despite this, resistance to PARPi commonly develops through diverse mechanisms, such as the acquisition of secondary BRCA1/2 mutations. Perhaps less well documented is that PARPi can impact both the tumour microenvironment and the immune response, through upregulation of the stimulator of interferon genes (STING) pathway, upregulation of immune checkpoints such as PD-L1, and by stimulating the production of pro-inflammatory cytokines. Whilst targeted immunotherapies have not yet found their place in the clinic for HGSOC, the evidence above, as well as ongoing studies exploring the synergistic effects of PARPi with immune agents, including immune checkpoint inhibitors, suggests potential for targeting the immune response in HGSOC. Additionally, combining PARPi with epigenetic-modulating drugs may improve PARPi efficacy, by inducing a BRCA-defective phenotype to sensitise resistant …
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