A Review: Genetic Mutations as a Key to Unlocking Drug Resistance in Cervical Cancer

Abstract

Cervical cancer is the fourth most common cancer in women. Advanced stage and metastatic disease are often associated with poor clinical outcomes. This substantiates the absolute necessity for high-throughput diagnostic and treatment platforms that are patient and tumour specific. Cervical cancer treatment constitutes multimodal intervention. Systemic treatments such as chemotherapy and/or focal radiotherapy are typically applied as neoadjuvant and/or adjuvant strategies. Cisplatin constitutes an integral part of standard cervical cancer treatment approaches. However, despite initial patient response, de novo or delayed/acquired treatment resistance is often reported, and toxicity is of concern. Chemotherapy resistance is associated with major alterations in genomic, metabolomic, epigenetic and proteomic landscapes. This results in imbalanced homeostasis associated with pro-oncogenic and proliferative survival, anti-apoptotic benefits, and enhanced DNA damage repair processes. Although significant developments in cancer diagnoses and treatment have been made over the last two decades, drug resistance remains a major obstacle to overcome.

Keywords: cervical cancer; cisplatin; genetic mutations; precision oncology; treatment resistance.

Figure 1.

Overview of cisplatin treatment resistance. (1) Decreased intracellular accumulation of platinum compounds; (2) Increased DNA damage repair; (3) Inactivation of apoptosis; (4) Epithelial-mesenchymal transition. Abbreviations: CTR1: Copper transporter 1; EMT: Epithelial-mesenchymal transition; MMR: Mismatch repair; NER: Nucleotide excision repair; PARP: Poly (ADP-ribose) polymerase. Created with BioRender.com.

Figure 2.

Genetic mutations contribute to cervical cancer progression. Several mutations (de novo or acquired) contribute to treatment resistance by preventing cancer cell death and instead promotes cancer progression. Currently, several inhibitors of these genetic mutations are being investigated in phase I and phase II clinical trials which could promote more favourable treatment responses in cancer patients. (1) During high-risk HPV integration, E6 can bind to and control the function of p53. E6 interacts with E6-associated protein (E6AP), which catalyzes multi-ubiquitination resulting in the breakdown of p53 once it binds to the dimeric complex. Mutated TP53 can also regulate the expression of chemo- and radioresistant genes, including MDR1. MDR1 mediates the resistance of tumour cells to various hydrophobic cytotoxic drugs. (2) E7 disrupts the interaction between Rb and E2F, resulting in the release of E2F in its transcriptionally active form. This E7-mediated conversion of E2F to its activator forms stimulates cell cycle activation and proliferation. (3) Transition from KRAS-GDP to KRAS-GTP (mutant KRAS) requires GAPs proteins. Downstream signalling of KRAS induces cellular proliferation. (4) PTEN is mainly involved as a negative regulator in the PI3K/AKT/mTOR pathway, however, once dysregulated, it promotes cell cycle activation/proliferation. Abbreviations: E2F: E2 promotor binding factor; ERK: Extracellular signal-regulated kinase; GAP: GTPase activating proteins; GDP: Guanosine diphosphate; GTP: Guanosine triphosphate; HPV: Human papilloma virus; KRAS: Kirsten rat sarcoma viral oncogene homolog; MEK: Mitogen-activated protein kinase; P: Phosphorylate; PTEN: Phosphatase and tensin homolog; RAF: Rapidly accelerated fibrosarcoma; Rb: Retinoblastoma. Created with Biorendor.com.