Development of resistance to FGFR inhibition in urothelial carcinoma via multiple pathways in vitro

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Alterations in fibroblast growth factor receptors (FGFRs) are prevalent in bladder and other cancers, leading to aberrant signaling.
• FGFR-targeted therapies are clinically available but frequently encounter treatment resistance.
• Understanding resistance mechanisms is crucial for developing effective and durable cancer treatments.

Purpose of the Study:

• To model and investigate the molecular mechanisms of acquired resistance to FGFR inhibitors in bladder cancer.
• To identify potential therapeutic vulnerabilities associated with resistance phenotypes.

Main Methods:

• Derivation of resistant bladder cancer cell lines through long-term culture with the FGFR inhibitor PD173074.
• Utilized expression profiling and whole-exome sequencing to analyze resistance-associated molecular alterations.
• Assessed sensitivity to alternative targeted therapies in resistant cell line derivatives.

Main Results:

• Identified diverse resistance mechanisms, including HRAS mutation and reversible drug-tolerant persister phenotypes.
• Observed upregulated IGF1R conferring sensitivity to linsitinib in one resistant line.
• Detected a YAP/TAZ signature associated with sensitivity to a YAP inhibitor (CA3) in another resistant line.
• Found that upregulation of some targets did not predict sensitivity to corresponding therapies.

Conclusions:

• The heterogeneity of resistance mechanisms and the prevalence of persister states pose significant challenges for personalized FGFR-targeted therapy in bladder cancer.
• The reversibility of certain resistance mechanisms suggests that intermittent treatment strategies or retreatment upon relapse may benefit some patients.