Emerging Therapeutics to Overcome Chemoresistance in Epithelial Ovarian Cancer: A Mini-Review

Abstract

Ovarian cancer is the fifth leading cause of cancer death among women and the most lethal gynecologic malignancy. One of the leading causes of death in high-grade serous ovarian cancer (HGSOC) is chemoresistant disease, which may present as intrinsic or acquired resistance to therapies. Here we discuss some of the known molecular mechanisms of chemoresistance that have been exhaustively investigated in chemoresistant ovarian cancer, including drug efflux pump multidrug resistance protein 1 (MDR1), the epithelial-mesenchymal transition, DNA damage and repair capacity. We also discuss novel therapeutics that may address some of the challenges in bringing approaches that target chemoresistant processes from bench to bedside. Some of these new therapies include novel drug delivery systems, targets that may halt adaptive changes in the tumor, exploitation of tumor mutations that leave cancer cells vulnerable to irreversible damage, and novel drugs that target ribosomal biogenesis, a process that may be uniquely different in cancer versus non-cancerous cells. Each of these approaches, or a combination of them, may provide a greater number of positive outcomes for a broader population of HGSOC patients.

Keywords: DNA damage and repair; chemoresistance; epithelial–mesenchymal transition; high-grade serous ovarian cancer; multidrug resistance protein 1 (MDR1); ribosome biogenesis.

Figure 1

Intrinsic versus acquired resistance. Mechanisms of intrinsic and/or acquired chemoresistance include extracellular matrix proteins, P-glycoprotein (P-gp) efflux pumps and ATP binding cassette (ABC) transporters, cytochrome p450 and glutathione transferases, poor vascularization, DNA damage insensitivity and repair, drug target alteration and upregulation of pro-survival anti-apoptotic factors. Abbreviations: adenosine diphosphate (ADP), adenosine triphosphate (ATP), B-cell lymphoma 2 (BCL-2), B-cell lymphoma-extra large (BCL-XL), myeloid cell leukemia 1 (MCL-1), X-linked inhibitor of apoptosis protein/cellular inhibitor of apoptosis (xIAP/cIAP).

Figure 2

Action and targeting of P-gp and MDR1 drug efflux pumps. Activation of MDR1/ABCB1 transcription leads to drug efflux and inhibition of cytochrome p450 isoenzymes. Chemosensitivity and cell death can be enhanced by inhibitors and siRNA targeted therapies. Abbreviations: adenosine triphosphate binding cassette-B1 (ABCB1) transporters; antisense oligonucleotide (ASO), cluster of differentiation 44 (CD44), multidrug resistance protein 1 (MDR1), small interfering RNA (siRNA).

Figure 3

Epithelial–mesenchymal transition. Upregulation of Snail, Slug, Zeb1 and Twist lead to changes in mesenchymal and stem cell markers including downregulation of E-cadherin, and upregulation of vimentin, N-cadherin, ALDH1 and endothelin-A. Abbreviations: aldehyde dehydrogenase-1 (ALDH1).

Figure 4

DNA damage and repair. PARP inhibitors in the presence of platinum-based chemotherapy and homologous recombination (HR) deficient DNA can induce synthetic lethality. TP53 mutated DNA can show cell cycle delay at the G2 phase, which can be inhibited by Wee1 kinase inhibitors to promote cell death and enhance chemosensitivity. Abbreviations: Gap 2 (G2); poly(ADP-ribose) polymerase-I (PARP I); tumor protein 53 (TP53).

Figure 5

Ribosomal biogenesis targeting. Inhibitors of the RNA polymerase I pre-initiation complex, such as CX-5461 and BMH-21, can inhibit ribosome production and availability. Some data suggests that cancer cells may be more susceptible to targeting this pathway than nontransformed cells. Abbreviations: selective factor 1 (SL1).