The PI3K/AKT/mTOR signaling pathway interferes with cell proliferation, survival, metabolism, and angiogenesis. Overactivation of this signal transduction is one of the hallmarks of several human cancers, usually traceable to genetic alterations like PIK3CA mutation, PTEN loss, or AKT amplification. Inhibition of the pathway therefore opens attractive therapeutic windows currently applied or being tested in clinical trials with drugs ranging from PI3K isoform-specific inhibitors to dual PI3K/mTOR inhibitors. Drug resistance mechanisms, feedback activation of parallel pathways, and toxicity are some roadblocks limiting their long-term efficacy. However, these can increasingly be addressed by the advent of combination therapies, biomarker-based patient selection, and new drug delivery systems. This review dwells on a comprehensive assessment of the biological significance of the PI3K/AKT/mTOR pathway in cancer, therapeutics in development, mechanisms mediating resistance, and emerging concepts that may help improve and broaden the clinical interventions in target therapy for oncology. Keywords: PI3K/AKT/mTOR pathway, cancer, targeted therapy, PI3K inhibitors, AKT inhibitors, mTOR inhibitors, resistance mechanisms, combination therapy, biomarkers.
Bhavani et al. (Wed,) studied this question.