Abstract
OBJECTIVE: This study aims to explore the persistent activation of the PI3K/AKT signaling pathway in various cancers, with a focus on upstream coactivators that drive tumor growth and contribute to therapeutic resistance. METHODS: An integrated overview of four disparate tumorigenic coactivators of PI3K/AKT signaling, namely, TMEPAI (a transmembrane adaptor protein), SALL4 (a zinc-finger transcription factor), TCL1B (an oncoprotein coactivator), and TGF-β (a cytokine ligand) was identified and analyzed through a comprehensive literature review. Their mechanistic insights, signaling interactions, and therapeutic opportunities were also summarized. RESULTS: The study outcomes demonstrate that each of these coactivators contributes to PI3K/AKT pathway hyperactivation and cancer progression through distinct mechanisms, such as the downregulation of negative regulators or direct enhancement of AKT activation. Emerging therapeutic approaches targeting these coactivators through gene silencing, small-molecule inhibitors, and peptide-based interventions were also outlined, along with associated challenges such as drug specificity, toxicity, and resistance. CONCLUSION: By synthesizing evidence across these diverse molecules, this review highlights the convergent impact of multiple molecular classes on the PI3K/AKT pathway and outlines future perspectives for leveraging these insights in targeted cancer therapies.