Emerging Roles for Mammalian Target of Rapamycin (mTOR) Complexes in Bladder Cancer Progression and Therapy

Simple Summary The mammalian target of rapamycin (mTOR) pathway promotes cell growth and metabolism in response to growth factors, nutrients, and cellular energy status. Dysregulation and mutation of the mTOR pathway can contribute to tumor initiation and progression. mTOR pathway abnormalities have been found in approximately 70% of urothelial carcinomas (UCs). This review summarizes recent advances in knowledge of the mTOR pathway, highlights the role of the mTOR pathway in UC, and explores the potential of the mTOR pathway as a therapeutic target in UC. This review also explores current preclinical studies and clinical trials targeting the mTOR pathway, and concludes with future directions of research that could more robustly define and target aberrant mTOR activity in bladder cancer. The mammalian target of rapamycin (mTOR) pathway regulates important cellular functions. Aberrant activation of this pathway, either through upstream activation by growth factors, loss of inhibitory controls, or molecular alterations, can enhance cancer growth and progression. Bladder cancer shows high levels of mTOR activity in approximately 70% of urothelial carcinomas, suggesting a key role for this pathway in this cancer. mTOR signaling initiates through upstream activation of phosphatidylinositol 3 kinase (PI3K) and protein kinase B (AKT) and results in activation of either mTOR complex 1 (mTORC1) or mTOR complex 2 (mTORC2). While these complexes share several key protein components, unique differences in their complex composition dramatically alter the function and downstream cellular targets of mTOR activity. While significant work has gone into analysis of molecular alterations of the mTOR pathway in bladder cancer, this has not yielded significant benefit in mTOR-targeted therapy approaches in urothelial carcinoma to date. New discoveries regarding signaling convergence onto mTOR complexes in bladder cancer could yield unique insights the biology and targeting of this aggressive disease. In this review, we highlight the functional significance of mTOR signaling in urothelial carcinoma and its potential impact on future therapy implications.

Automated summary

The mammalian target of rapamycin (mTOR) pathway plays a crucial role in cell growth and metabolism. Dysregulation of this pathway can promote cancer growth and progression. Approximately 70% of bladder cancer (UC) cases show abnormal mTOR activity, indicating its key role in this cancer. This review highlights the importance of mTOR signaling in UC and its potential implications for future therapy. Despite extensive research on molecular alterations of the mTOR pathway in bladder cancer, there has been limited success in mTOR-targeted therapy. Further understanding of the signaling convergence onto mTOR complexes in bladder cancer may provide valuable insights for the treatment of this aggressive disease.