Activation of the PI3K/AKT/mTOR signaling pathway in bladder cancer pathogenesis and its therapeutic significance.

Bladder cancer is one of the most frequently observed cancer types globally. Urothelial bladder carcinoma (UBC) is the most common histologic subtype. Around 25% of patients present with muscle-invasive bladder cancer (MIBC) or metastatic disease, which are associated with poor prognosis. The PI3K/AKT/mTOR signaling pathway is an essential pathway for different cellular processes such as cell proliferation, survival, motility and metabolism. Aberrant activation of this pathway has been implicated in the development of UBC, which occurs in more than 40% of urothelial carcinomas of the bladder. Considering the frequent activation of this signaling pathway in UBC and its crucial role in tumorigenesis, targeting this pathway is an attractive therapeutic strategy in bladder cancer treatment. Several preclinical and clinical studies have provided insights into the therapeutic potential of targeting this pathway. This review initially provides an overview of the PI3K/AKT/mTOR signaling followed by the role of activation of this pathway in bladder cancer development. Then, it discusses the preclinical studies that investigated diverse pathway inhibitors and their efficacy in different bladder cancer models. Finally, relevant clinical trials that were conducted are summarized, with their outcomes and challenges.