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.
Highlights
Ovarian cancer remains a devastating diagnosis with an overall survival rate of ~40%, making it the fifth leading cause of cancer death in women and the most lethal gynecologic malignancy [1,2,3]
Until recently most preclinical studies have been performed on cell lines that are more of an endometrioid subtype than serous, and may not be applicable to the tumor protein 53 (TP53)-mutant driven serous subtype [8]
Studies have elucidated many of the mechanisms that underlie the development of chemotherapy resistance in high-grade serous ovarian cancers (HGSOC) and successfully targeting these systems in the clinic is critical in extending patient survival
Summary
Ovarian cancer remains a devastating diagnosis with an overall survival rate of ~40%, making it the fifth leading cause of cancer death in women and the most lethal gynecologic malignancy [1,2,3]. EOC can develop as high-grade serous, low-grade serous, endometrioid, clear cell and mucinous histotypes. A more important distinction is high-grade versus low-grade cytologic subtypes, as low-grade serous ovarian cancers are more slow-growing, but more chemoresistant, than high-grade serous ovarian cancers (HGSOC). This review of chemoresistance will focus on HGSOC as it is the dominant subtype seen in the clinic. Until recently most preclinical studies have been performed on cell lines that are more of an endometrioid subtype than serous, and may not be applicable to the tumor protein 53 (TP53)-mutant driven serous subtype [8]. Studies have elucidated many of the mechanisms that underlie the development of chemotherapy resistance in HGSOC (for reviews see [13,14,15,16,17]) and successfully targeting these systems in the clinic is critical in extending patient survival. This review will focus on HGSOC chemoresistance and emerging therapies that may show promise in mitigating and possibly defeating it
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