Characterization and treatment of gemcitabine‐ and cisplatin‐resistant bladder cancer cells with a pan‐RAS inhibitor

Abstract

Combination chemotherapy with gemcitabine and cisplatin (GC) is recommended as the primary treatment for advanced bladder cancer (BC). However, the benefits of this approach are limited owing to the acquisition of drug resistance. Here, we found that gemcitabine‐resistant and cisplatin‐resistant BCs do not exhibit cross‐resistance, and that these BCs exhibit different mRNA patterns, as revealed using RNA sequence analysis. To overcome drug resistance, we used the newly developed pan‐RAS inhibitor Compound 3144. Compound 3144 inhibited cell viability through suppression of RAS‐dependent signaling in gemcitabine‐ and cisplatin‐resistant BCs. RNA sequencing revealed that several genes and pathways, particularly those related to the cell cycle, were significantly downregulated in Compound 3144‐treated BCs. These findings provide insights into potential therapeutic strategies for treating BC.

Keywords

• bladder cancer
• cisplatin resistance
• gemcitabine resistance
• pan‐RAS inhibitor
• RAS