PDK1 signaling in cancer: Current status and future perspectives.

Abstract

Dysregulation of signaling pathways governing cell growth, survival, metabolism, angiogenesis, invasion, metastasis, and therapeutic response drives cancer progression. The AGC family of kinases, such as AKT, S6K, SGK, RSK, and PKC, is important for downstream signaling. The 3-phosphoinositide-dependent protein kinase-1 protein (PDK1), encoded by the PDPK1 gene, phosphorylates activation-loop residues in these kinases and links phosphoinositide signaling to cellular growth, survival, metabolism, and transformation. The structure, regulation, cancer-associated functions, and therapeutic targeting of PDK1 are critically reviewed, with a focus on the pleckstrin homology domain, PIF pocket-mediated substrate docking, the kinase domain, and reported non-catalytic interactions. Experimental results from breast, lung, gastric, liver, hematological, and melanoma models suggest that dysregulated PDK1 signaling can increase the output of the PI3K-AKT-mTOR pathway, invasion, metabolic adaptation, and resistance to specific hormonal, chemotherapeutic, and targeted therapies. In some preclinical models, genetic suppression of PDK1 using siRNA, shRNA, or CRISPR-based methods has been shown to slow tumor cell growth and restore drug sensitivity. However, PDK1 remains an unvalidated therapeutic target in the clinic. There is no selective PDK1 inhibitor that has been clinically approved, and most pharmacological candidates are based on biochemical and cellular data. There is limited genetic evidence and in vivo evidence, and no validated clinical evidence specific to PDK1. Emerging PIF-pocket ligands, dual-site inhibitors, allosteric modulators, and protein-degradation strategies are therefore investigational strategies that need to be improved in terms of selectivity, pharmacokinetic characterization, tumor-context validation, and biomarker-guided evaluation.