KIF18A and CDK1 as combined therapeutic targets in cervical and endometrial carcinomas: based on bioinformatics analysis and in vitro experiments

Mengjie Wang; David Lukanovic; Fabio Barra; Aoli Lei

doi:10.21037/tcr-24-1831

KIF18A and CDK1 as combined therapeutic targets in cervical and endometrial carcinomas: based on bioinformatics analysis and in vitro experiments

Transl Cancer Res. 2024 Dec 31;13(12):6880-6894. doi: 10.21037/tcr-24-1831. Epub 2024 Dec 18.

Authors

Mengjie Wang¹, David Lukanovic^{2

3}, Fabio Barra^{4

5}, Aoli Lei⁶

Affiliations

¹ Department of Pharmacy, Shaanxi Cancer Hospital, Xi'an, China.
² Division of Gynecology and Obstetrics, Department of Gynecology, Ljubljana University Medical Center, Ljubljana, Slovenia.
³ Department of Gynecology and Obstetrics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
⁴ Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy.
⁵ Unit of Obstetrics and Gynecology, P.O. "Ospedale del Tigullio"-ASL4, Genoa, Italy.
⁶ Department of Gynecology, the First Hospital of Weinan City, Weinan, China.

Abstract

Background: Chromosomal instability (CIN) has been identified as a factor that increases the susceptibility of tumor cells to kinesin family member 18A (KIF18A) inhibitors. Limited research exists on genes that are associated with sensitization to KIF18A inhibitors (KIF18Ais). Our study aimed to identify a gene linked to heightened sensitivity to KIF18Ais in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) and uterine corpus endometrial carcinoma (UCEC).

Methods: The Cancer Genome Atlas (TCGA) and X2K Appyter databases were used to analyze potential kinases associated with KIF18A-related genes in CESC and UCEC. In vitro assessments, such as Cell Counting Kit-8 (CCK-8), transwell, and terminal-deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assays, were performed to evaluate the combined effects of KIF18A and cyclin-dependent kinase 1 inhibitors (CDK1is) in CESC and UCEC cell lines.

Results: Our findings indicated that the combination of KIF18A with kinases may potentially augment the efficacy of KIF18Ais, given its close involvement in cell cycle and chromosome segregation. Through bioinformatics analysis, we observed a significant up-regulation of CDK1 expression in CESC and UCEC, which exhibited a strong correlation with KIF18A expression. Our hypothesis regarding the potential of CDK1 as a combination therapeutic target for KIF18A was supported by our cell experiments, which demonstrated that inhibition of CDK1 notably increased the sensitivity of CESC and UCEC cells to KIF18Ais. The combined use of CDK1is and KIF18Ais exhibited a synergistic effect in inhibiting cell migration and inducing apoptosis in CESC and UCEC cells.

Conclusions: This study provides evidence that targeting both KIF18A and CDK1 exerts synergistic anti-tumor effects in CESC and UCEC via inhibiting cell proliferation and migration and inducing apoptosis, suggesting a promising therapeutic strategy for these cancers.

Keywords: Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC); cyclin-dependent kinase 1 (CDK1); kinesin family member 18A (KIF18A); synergistic effect; uterine corpus endometrial carcinoma (UCEC).