Spotlight on New Hallmarks of Drug-Resistance towards Personalized Care for Epithelial Ovarian Cancer

Abstract

Epithelial ovarian cancer (EOC) is the deadliest gynecological malignancy worldwide. Despite the latest advances, a major clinical issue in EOC is the disappointing prognosis related to chemoresistance in almost one-third of cases. Drug resistance relies on heterogeneous cancer stem cells (CSCs), endowed with tumor-initiating potential, leading to relapse. No biomarkers of chemoresistance have been validated yet. Recently, major signaling pathways, micro ribonucleic acids (miRNAs), and circulating tumor cells (CTCs) have been advocated as putative biomarkers and potential therapeutic targets for drug resistance. However, further investigation is mandatory before their routine implementation. In accordance with the increasing rate of therapeutic efforts in EOC, the need for biomarker-driven personalized therapies is growing. This review aims to discuss the emerging hallmarks of drug resistance with an in-depth insight into the underlying molecular mechanisms lacking so far. Finally, a glimpse of novel therapeutic avenues and future challenges will be provided.

Keywords: biomarkers; drug-resistance; epithelial ovarian cancer.

Figure 1

Factors implicated in EOC stem cell heterogeneity and the complex relationships between them. The overall heterogeneity of EOC is deemed to be the outcome of several interconnected mechanisms of diversification, mostly involving the subpopulation of CSCs both directly and indirectly. These mechanisms establish several layers of tumor complexity acting throughout the entire tumor evolution path. Adapted from J. Hatina et al. Ovarian Cancer Stem Cell Heterogeneity. In A. Birbrair (Ed.), Stem Cells Heterogeneity in Cancer (pp. 201–216) [8].

Figure 2

Potential targeting approaches to eradicate drug-resistant CSCs in EOC. Potential targets for the elimination of ovarian cancer stem cells. CAF: cancer-associated fibroblast, VEGF: vascular endothelial growth factor, VEGFR: VEGF receptor, EMT: epithelial to mesenchymal transition, Magma: mitochondrial associated granulocyte macrophage colony stimulating factor, LncRNA: long noncoding RNA, EZH2: enhancer of zeste homolog 2, TAM: tumor-associated macrophage, PD1: programmed death 1, PDL1: programmed death-1 (PD-1) ligand1, PARP: poly (ADP-ribose) polymerase 1, DKK1: Dickopf 1, GSI: gamma secretase inhibitor. Adapted from Saha, S., Parte, S., Roy, P., and Kakar, S. S. (2021). Ovarian cancer stem cells: Characterization and role in tumorigenesis. Advances in Experimental Medicine and Biology, 1330, 151–169 [24,34].

Figure 3

Overview of mechanisms of drug-resistance in EOC. Abbreviations. CTLA-4: cytotoxic T lymphocyte-associated antigen 4. DNA: deoxyribonucleic acid. MDSC: myeloid-derived suppressor cell. PD-1: programmed cell death protein 1. PD-L1: programmed cell death protein ligand 1. TAM: tumor-associated macrophage. Treg: regulatory T cell. Adapted from Marchetti C. et al. Chemotherapy resistance in epithelial ovarian cancer: Mechanisms and emerging treatments. Seminars in Cancer Biology 77 (2021) 144–166 [6].