Signaling networks and MiRNA crosstalk in ovarian cancer chemoresistance

Abstract

Epithelial ovarian cancer (EOC), accounting for 90-95% of all ovarian cancer (OC) cases, is the most lethal gynaecological malignancy, primarily due to late-stage diagnosis and the development of chemoresistance. While initial responses to Platinum- and Taxane-based chemotherapy are favorable, nearly 70% of patients relapse within five years. Although signaling pathways such as PI3K/AKT, MAPK, NF-κB, Notch, and Wnt/β-catenin have been individually studied in the context of chemoresistance, recent evidence highlights the importance of dynamic feedback loops and crosstalk among these networks in sustaining the resistant phenotype. Moreover, dysregulated microRNAs (miRNAs), as post-transcriptional regulators, fine-tune these pathways, creating self-sustaining circuits that promote drug efflux, inhibit apoptosis, and maintain cancer stemness. Reciprocal regulation between miRNAs and signaling components establishes robust networks that amplify chemoresistant phenotypes. The review provides a comprehensive overview of the molecular mechanisms driving chemoresistance, emphasising critical elements of signalling pathways and associated miRNAs that contribute to resistance and may function as biomarkers or therapeutic targets to mitigate chemoresistance. To improve clinical outcomes, future research should focus on identifying resistance-associated miRNA signatures and targeting nodal points within miRNA-signaling networks, thereby enabling the development of personalized therapies to overcome drug resistance in EOC.

Keywords: Chemotherapy; Drug resistance; MiRNA; Ovarian cancer; Recurrence; Signaling pathway; Tumorigenesis.

Fig. 1

Molecular mechanisms and signaling components contributing to Platinum and Taxane resistance in EOC. The diagram illustrates key mediators associated with resistance to Platinum (left) and Taxane (right) chemotherapy agents. Central mechanisms include reduced apoptosis, enhanced DNA repair, decreased microtubule stability, EMT, and increased drug efflux. TGFBI, Transforming Growth Factor Beta-Induced protein; FASN, Fatty Acid Synthase; RUNX1, Runt-Related Transcription Factor 1; BMI1, B Lymphoma Mo-MLV Insertion Region 1 Homolog; HDAC1, Histone Deacetylase 1; XIAP, X-linked Inhibitor of Apoptosis Protein; CDK12, Cyclin-Dependent Kinase 12; MSX1, Msh Homeobox 1; BMP9, Bone Morphogenetic Protein 9; JAG1, Jagged Canonical Notch Ligand 1; CPT1A, Carnitine Palmitoyltransferase 1 A; SCD, Stearoyl-CoA Desaturase; MCL1, Myeloid Cell Leukemia 1; PLK1, Polo-Like Kinase 1; SYK, Spleen Tyrosine Kinase; CCL2, C-C Motif Chemokine Ligand 2; CAFs, Cancer-Associated Fibroblasts; TLR4, Toll-Like Receptor 4; SAC, Spindle Assembly Checkpoint; MyD88, Myeloid Differentiation Primary Response 88

Fig. 2

Crosstalk among major signaling pathways mediating chemoresistance in EOC. The diagram illustrates the complex interplay between major signaling pathways in promoting chemoresistance in EOC. Activation of these pathways drives tumor-promoting processes like EMT, apoptosis inhibition, angiogenesis, extracellular matrix remodeling, inflammation, and uncontrolled proliferation. Key components that serve as convergence points represent promising targets for therapeutic intervention, aiming to overcome resistance through the inhibition of multiple resistance-driving pathways

Fig. 3

Dysregulated signaling pathways and associated miRNAs contributing to chemoresistance in EOC. Specific miRNAs that are upregulated (↑, blue) or downregulated (↓, red) in Platinum or Taxane resistant EOC are mapped alongside each pathway. These miRNAs modulate pathway activity, thereby influencing therapeutic resistance, and represent potential targets for overcoming drug resistance