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Review
. 2019 Apr;23(4):2303-2313.
doi: 10.1111/jcmm.14133. Epub 2019 Jan 22.

PARP inhibitors in ovarian cancer: Sensitivity prediction and resistance mechanisms

Xuan Jiang  1 , Xiaoying Li  1 , Weihua Li  1 , Huimin Bai  1 , Zhenyu Zhang  1
Affiliations
Review

PARP inhibitors in ovarian cancer: Sensitivity prediction and resistance mechanisms

Xuan Jiang et al. J Cell Mol Med. 2019 Apr.

Abstract

Poly (ADP-ribose) polymerase (PARP) inhibitors have provided great clinical benefits to ovarian cancer patients. To date, three PARP inhibitors, namely, olaparib, rucaparib and niraparib have been approved for the treatment of ovarian cancer in the United States. Homologous recombination deficiency (HRD) and platinum sensitivity are prospective biomarkers for predicting the response to PARP inhibitors in ovarian cancers. Preclinical data have focused on identifying the gene aberrations that might generate HRD and induce sensitivity to PARP inhibitors in vitro in cancer cell lines or in vivo in patient-derived xenografts. Clinical trials have focused on genomic scar analysis to identify biomarkers for predicting the response to PARP inhibitors. Additionally, researchers have aimed to investigate mechanisms of resistance to PARP inhibitors and strategies to overcome this resistance. Combining PARP inhibitors with HR pathway inhibitors to extend the utility of PARP inhibitors to BRCA-proficient tumours is increasingly foreseeable. Identifying the population of patients with the greatest potential benefit from PARP inhibitor therapy and the circumstances under which patients are no longer suited for PARP inhibitor therapy are important. Further studies are required in order to propose better strategies for overcoming resistance to PARP inhibitor therapy in ovarian cancers.

Keywords: BRCA1/2; PARP inhibitor; homologous recombination deficiency; ovarian cancer; resistance mechanism.

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Conflict of interest statement

The authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1
According to The Cancer Genome Atlas (TCGA), ovarian cancers can be classified as HR‐proficient and other (34%), possibly HR‐deficient (10%) (including those with alterations in 42 other potentially relevant HR genes, such as BLM, ERCC4, TP53BP1, RPA1 and XRCC3) and HR‐deficient (56%) (including those with alterations of BRCA1/2; the amplification or mutation of EMSY; the deletion of PTEN, Fanconi anemia genes [including FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, PALB2 and C19orf40], core HR RAD genes [including RAD50, RAD51, RAD51C, RAD51L1, RAD51L3, RAD52, RAD54B and RAD54L] or HR‐related DNA damage response genes [including ATM, ATR, CHEK1 and CHEK2])27, 36
Figure 2
Figure 2
The molecular process of DNA damage repair associated with PARP inhibitor sensitivity and resistance. 1) During the repair of DSBs by NHEJ, damage is recognized and bound by Ku70‐Ku80 heterodimers, DNA‐PKcs and Artemis are activated, and XRCC4 and DNA ligase‐IV are recruited to complete DNA end joining. NHEJ occurs throughout the cell cycle and directly ligates the ends of a DSB. The loss of the abovementioned crucial proteins in the NHEJ pathway might induce resistance to PARP inhibitors. 2) During the repair of DSBs by HR, DNA lesions are recognized by the MRE11‐NBS1‐RAD50 (MRN) complex, and DNA end resection is initiated. In a PALB2‐dependent fashion, BRCA2 is recruited, which loads RAD51 onto the DNA to mediate strand invasion on the homologous sister chromatid. HR occurs mainly in the S and G2 phases. The switch between HR and NHEJ depends on the activity of S phase CDKs, which phosphorylate CtIP in order to activate the MRN complex and stimulate DNA end resection, which is regulated by 53BP1, REV7 and RIF1. The abovementioned crucial proteins in the HR pathway might thus affect PARP inhibitor sensitivity. 3) In addition, the cell cycle checkpoint pathway and the FA‐BRCA1 pathway are involved in HR, and crucial proteins in these pathways are associated with PARP inhibitor sensitivity27, 46
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