Evaluating Oncogenic Drivers and Therapeutic Potential of the PI3K/AKT/mTOR Pathway in Hepatocellular Carcinoma: An Overview of Clinical Trials

Abstract

Hepatocellular carcinoma (HCC) is the most common primary liver tumor and the third leading cause of cancer-related mortality globally. The phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is critically involved in HCC pathogenesis, stimulating uncontrolled cell proliferation, survival, and tumor progression. The overactivation of this pathway is strongly linked to poor prognosis, making it a crucial target for therapeutic intervention. The oncogenic roles of PI3K/AKT/mTOR components in HCC have been highlighted, noting that class I PI3K deregulation, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) upregulation, and mTOR overexpression could be associated with poor HCC outcomes. To the best of our knowledge, this is the first time that the clinical trials investigating PI3K/AKT/mTOR inhibitors in HCC are analyzed. Accordingly, there is a predominance of mTOR inhibitors, with everolimus being the most frequently utilized drug. However, only 10% of studies advanced to phase III or IV, predominantly involving mTOR inhibitors. Challenges such as adverse events like hyperglycemia and bone marrow suppression, as well as the emergence of treatment resistance, have hindered the success of these therapies. Combination therapies, particularly those involving mitogen-activated protein kinase kinase (MEK) inhibitors, chemotherapy, immune checkpoint inhibitors, and vascular endothelial growth factor (VEGF) inhibitors, have shown promise in overcoming these challenges. Recent advances in nanotechnology offer the potential for improving drug delivery and reducing toxicity.