Development of a novel treatment based on PKMYT1 inhibition for cisplatin-resistant bladder cancer with
Wataru Fukumoto1, Shunsuke Okamura1, Motoki Tamai1
1Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-8520, Japan.
Background:
Chemotherapy including cisplatin is recommended for the treatment of advanced bladder cancer, but its effectiveness is limited due to the acquisition of drug resistance. Although several mechanisms of cisplatin resistance have been reported, there are still many unknowns, and treatment of cisplatin-resistant bladder cancer remains difficult. Accordingly, in this study, we aimed to identify and characterize microRNAs involved in cisplatin resistance.
Methods:
Small RNA sequencing analysis was performed to search for microRNAs related to cisplatin resistance. The identified microRNAs were then characterized using gain-of-function studies, sensitivity analysis, target gene analysis, and cellular assays.
Results:
We identified miR-424-5p as a candidate microRNA that was downregulated in cisplatin-resistant strains compared with parental strains. Notably, in gain-of-function studies, miR-424-5p suppressed the proliferative ability of cisplatin-resistant bladder cancer (CDDP-R BC). Furthermore, miR-424-5p restored sensitivity to cisplatin. RNA sequence analysis revealed seven candidate genes targeted by this microRNA. Among them, cyclin E1 (CCNE1) was chosen for subsequent analyses because its expression was upregulated in cisplatin-resistant cells compared with parental cells and because recent studies have shown that CCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition. Therefore, we performed functional analysis using the PKMYT1 inhibitor RP-6306 and demonstrated that RP-6306 inhibited cell growth through suppression of mitotic entry and restored cisplatin sensitivity in CDDP-R BC.
Conclusions:
Overall, our findings provided insights into the development of novel therapeutic strategies for CDDP-R BC.
Insights
Researchers identified miR-424-5p as a key microRNA in cisplatin resistance in bladder cancer. Restoring miR-424-5p re-sensitized cancer cells to chemotherapy, offering new therapeutic avenues.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Cisplatin chemotherapy is standard for advanced bladder cancer but faces limited efficacy due to acquired drug resistance.
- Mechanisms of cisplatin resistance are not fully understood, complicating treatment for cisplatin-resistant bladder cancer (CDDP-R BC).
Purpose of the Study:
- To identify and characterize microRNAs (miRNAs) implicated in cisplatin resistance in bladder cancer.
- To explore potential therapeutic targets for overcoming drug resistance.
Main Methods:
- Small RNA sequencing was employed to identify candidate miRNAs associated with cisplatin resistance.
- Gain-of-function studies, sensitivity analyses, target gene identification, and cellular assays were performed for characterization.
Main Results:
- miR-424-5p was found to be downregulated in cisplatin-resistant bladder cancer cells.
- Restoring miR-424-5p suppressed proliferation and re-sensitized CDDP-R BC to cisplatin.
- CCNE1 was identified as a target gene; inhibition of PKMYT1 kinase with RP-6306 suppressed growth and restored cisplatin sensitivity.
Conclusions:
- The study identified miR-424-5p as a crucial factor in cisplatin resistance.
- Findings suggest novel therapeutic strategies targeting miR-424-5p or related pathways for CDDP-R BC.
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