Abstract
Despite significant improvements in surgical and medical management, high grade serous ovarian cancer (HGSOC) still represents the deadliest gynecologic malignancy and the fifth most frequent cause of cancer-related mortality in women in the USA. Since DNA repair alterations are regarded as the “the Achille’s heel” of HGSOC, both DNA homologous recombination and DNA mismatch repair deficiencies have been explored and targeted in epithelial ovarian cancers in the latest years. In this review, we aim at focusing on the therapeutic issues deriving from a faulty DNA repair machinery in epithelial ovarian cancers, starting from existing and well-established treatments and investigating new therapeutic approaches which could possibly improve ovarian cancer patients’ survival outcomes in the near future. In particular, we concentrate on the role of both Poly (ADP-ribose) Polymerase (PARP) inhibitors (PARPis) and immune checkpoint inhibitors in HGSOC, highlighting their activity in relation to BRCA1/2 mutational status and homologous recombination deficiency (HRD). We investigate the biological rationale supporting their use in the clinical setting, pointing at tracking their route from the laboratory bench to the patient’s bedside. Finally, we deal with the onset of mechanisms of primary and acquired resistance to PARPis, reporting the pioneering strategies aimed at converting homologous-recombination (HR) proficient tumors into homologous recombination (HR)-deficient HGSOC.
Highlights
In order to evaluate the prevalence of BRCA reversion mutations in high grade serous ovarian cancer (HGSOC), Lin et al [64] conducted targeted next-generation sequencing (NGS) of circulating cell-free DNA extracted from pre-treatment and post-progression plasma in patients with deleterious germline or somatic BRCA mutations treated with the Poly (ADP-ribose) Polymerase (PARP) inhibitor Rucaparib
Attractive molecular targets are constituted by: the heat shock protein 90 (HSP90), which is an ATP-dependent molecular chaperone mediating the maturation, stability and activation of several hundreds of different proteins, including cell cycle regulators, such as cyclin-dependent kinase 1 (CDK1), and key proteins essential for DNA repair, such as BRCA1, BRCA2, and RAD51 [76]; cyclin D1, a component of the cell cycle machinery which is involved in homologous recombination (HR)-mediated DNA repair and is overexpressed in 14–89% of ovarian cancer cases, resulting associated with a poorer prognosis [77]; vascular endothelial growth factor receptor 3 (VEGFR3), in which inhibition resulted in cell cycle arrest, decrease of both BRCA1 and BRCA2 expression, and significant increase of chemosensitivity in resistant ovarian cell lines in which a BRCA2 mutation had reverted to wild-type [78]
Huge preclinical and clinical efforts have been made to cope with these issues, focusing on DNA repair deficiency and strategies to exploit this distinctive feature, which is regarded as “the Achille’s heel” of HGSOC
Summary
High-grade serous epithelial ovarian cancer (HGSOC) represents the deadliest malignancy among gynecologic cancers and achieves the fifth rank among the most frequent causes of cancer-related mortality in women in the United States [1]. Despite initial response to platinum-based chemotherapy, most patients with this type of cancer experience disease relapse and develop platinum resistance. This is strictly related both to extensive intratumoral heterogeneity in primary high-grade serous carcinomas (accounting for about 70% of EOCs) and spatial and temporal genomic evolution under the selective pressure of medical treatments [3,4,5]. 50% indicates of HGSOC, repair defects are and pathways involved in DNA repair contribute to impairment of homologous recombination regarded as the “Achille’s heel”damage of this group of malignancies [1,6]. Implicated in HGSOC genetic instability (i.e., DNA mismatch repair) [8,9,10]
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