Platinum-resistant ovarian cancer: From drug resistance mechanisms to liquid biopsy-based biomarkers for disease management

Abstract

Resistance to platinum-based chemotherapy is a major clinical challenge in ovarian cancer, contributing to the high mortality-to-incidence ratio. Management of the platinum-resistant disease has been difficult due to diverse underlying molecular mechanisms. Over the past several years, research has revealed several novel molecular targets that are being explored as biomarkers for treatment planning and monitoring of response. The therapeutic landscape of ovarian cancer is also rapidly evolving, and alternative therapies are becoming available for the recurrent platinum-resistant disease. This review provides a snapshot of platinum resistance mechanisms and discusses liquid-based biomarkers and their potential utility in effective management of platinum-resistant ovarian cancer.

Keywords: Biomarkers; DNA repair; Epigenetic; Liquid biopsy; Ovarian cancer; Platinum drugs; Platinum resistance.

Figure 1.. Mechanisms underlying platinum resistance in ovarian cancer.

(A) Dysregulation of transporters associated with cisplatin/carboplatin leads to the reduced influx and increased efflux. (B) GSH and metallothionein mediate the inactivation of platinum compounds via the formation of drug conjugates. (C) Interaction between integrin and ECM promotes platinum resistance by inducing DNA damage repair proteins and CSC genes. (D) Upregulation of DNA damage repair proteins such as BRCA1 enables cancer cells to repair the DNA damage induced by platinum-based drugs and become resistant. (E) The upregulation of EGFR enhances the activity of DNMTs and leads to global methylation and downregulation of proteins regulating proliferation, migration, and invasion. (F) HDACs downregulate genes responsible for apoptosis and proliferation. (G) Inhibition of Wnt signaling mediated through the binding of Dishevelled to TMEM88 leads to cell dormancy and thus resists the action of the cytotoxic drugs. MT=Metallothionein; DSH=Dishevelled; FAK=focal adhesion kinase; ILK=Integrin-linked kinase; OCT=organic cation transporter; GSH=Glutathione; GS-X=Glutathione conjugate export pump; GSK= Glycogen synthase kinase 3; DNMT= DNA Methyltransferase; HDAC=Histone deacetylases; TMEM=Transmembrane Protein 88; EGFR=Epidermal Growth Factor Receptor

Figure 2.. Biomarkers of platinum-resistant ovarian cancer.

Molecular analysis of clinical specimens and laboratory studies have identified several molecular alterations associated with platinum-resistant ovarian cancer. These signature alterations can be exploited as molecular biomarkers to predict the nature of platinum resistance and monitor the response of ovarian cancer to therapy.