Targeting mTOR Kinase for Cancer Treatment: A Comprehensive Review With Clinical Insights

Cancer remains a significant global health challenge, with increasing incidence and mortality rates worldwide. The mechanistic target of rapamycin (mTOR) pathway, a central regulator of cell growth, proliferation, metabolism, and survival, has emerged as a promising therapeutic target in cancer. Dysregulation of mTOR signaling is implicated in various cancers, including breast, colon, lung, renal cell carcinoma, and multiple myeloma, making it an attractive target for inhibition. This review provides a comprehensive analysis of mTOR-targeted therapies, focusing on the clinical outcomes, efficacy, safety, and adverse effects of mTOR inhibitors. We explore the mechanisms of mTOR regulation, the impact of mTOR mutations on drug sensitivity, and the development of resistance to mTOR inhibitors. The review also highlights the potential of combination therapies and next-generation inhibitors to overcome resistance and improve therapeutic outcomes. Key mTOR inhibitors, including rapalogs (e.g., sirolimus, everolimus) and ATP-competitive inhibitors (e.g., MLN0128, PP242), are discussed in detail, along with their clinical applications and limitations. Additionally, we summarize the findings from major clinical trials, including FDA-approved mTOR inhibitors like everolimus and temsirolimus, and non-FDA-approved inhibitors such as sapanisertib and ridaforolimus. The review underscores the importance of understanding mTOR signaling and its role in cancer progression, offering insights into the future of mTOR-targeted therapies in oncology.