Chapter 3 - Drug resistance in gynecologic cancers: Findings and underlying mechanisms

Abstract

Drug resistance is a serious issue in treating common and lethal gynecologic cancers like cervical, endometrial, and ovarian cancers. It causes the failure of cancer treatment and tumor relapse, at the cellular and genetic levels. The commonly used FDA-approved chemotherapy treatments are taxanes (paclitaxel) and platinums (carboplatin and cisplatin) for ovarian cancer; cisplatin, carboplatin, gemcitabine, paclitaxel, and bevacizumab for advanced-stage cervical cancer; and platinum, taxanes, and doxorubicin for endometrial cancer. Decrease of intracellular accumulation of chemotherapy agents by acting on drug efflux and influx mechanisms is an important mechanism for developing resistance to chemotherapy. Signaling pathways like MAPK, PI3K, and mTOR help in regulating survival of cell, proliferation, and growth, contributing to resistance of drugs. The treatment of gynecologic cancers is affected by affecting the membrane transporter, cell death, and apoptosis. The roles of oncogenes, tumor-suppressor genes, and some proteins such as vimentin, connexin-32 (Cx-32), and tumor necrosis factor-associated protein 1 (TRAP-1) are being investigated to look for an involvement in drug resistance mechanisms. Other mechanisms leading to drug resistance are DNA repair mechanisms, cancer stem cell resistance, epithelial-mesenchymal transition activation, microRNAs (miRNAs), and circular RNAs (circRNAs). There are possibilities of other mechanisms of resistance, which is yet to be completely understood. This understanding is crucial in identifying possible biomarkers and monitoring the pattern of resistance and development of novel and effective targeting therapies to ultimately prevent failure of treatment.