ACK1/TNK2 kinase: molecular mechanisms and emerging cancer therapeutics

Activated CDC42-associated kinase 1 (ACK1), encoded by the TNK2 gene, is a cytoplasmic non-receptor tyrosine kinase whose aberrant activation correlates positively with cancer severity. Recent research has revealed the functional relevance of this oncokinase - it is an epigenetic regulator that drives cancer progression in multiple malignancies. Although ACK1 is an attractive target for therapeutic intervention, incomplete knowledge of its diverse signaling mechanisms and the lack of specific inhibitors have challenged its clinical success. We summarize recent breakthroughs in understanding ACK1 regulation and cellular signaling, and shed light on its immunomodulatory role in balancing T cell activation. We provide a comprehensive overview of preclinical, proof-of-concept studies of potent ACK1-targeting small-molecule inhibitors that are expected to enter clinical trials for cancer patients.