Molecular Mechanisms of Targeted Therapy Resistance in Genitourinary Tumors: A Path to New Therapeutic Horizons

Targeted therapies have transformed the treatment of genitourinary (GU) malignancies, particularly renal cell carcinoma (RCC), offering significant clinical benefits. However, therapy resistance, driven by intrinsic tumor characteristics and acquired mechanisms, frequently limits their effectiveness. This review comprehensively examines targeted therapies in GU tumors, focusing on their clinical impact and the molecular basis of resistance. While RCC has shown substantial improvements in overall survival, other GU tumors like prostate and bladder cancer have experienced more modest gains due to molecular heterogeneity and complex resistance pathways. These resistance mechanisms are diverse, including genomic alterations, epigenetic modifications, tumor microenvironment influences (immunosuppressive cells, angiogenesis), activation of alternative signaling pathways (PI3K/AKT, MAPK), and metabolic reprogramming. Intratumoral and metastatic site heterogeneity further contribute to resistant subclones. Current strategies to combat resistance involve developing next-generation agents, combination therapies (immunotherapy with TKIs), and personalized medicine guided by genomic profiling and biomarkers like PD-L1, TMB, and ctDNA. Liquid biopsies are increasingly used for real-time monitoring of resistance. Translational research focuses on innovative clinical trial designs (adaptive, basket, umbrella) and real-world evidence. Multidisciplinary collaborations, addressing undertreated populations, and navigating regulatory and cost challenges are crucial. Future directions include breakthroughs in NGS and single-cell analysis, big data and machine learning for predictive modeling, organoids and PDXs for preclinical studies, and novel TME-directed therapies. Ultimately, a more profound understanding of resistance mechanisms and innovative approaches will lead to more effective, personalized, and durable treatments for GU tumors, redefining clinical paradigms and improving patient outcomes.