ACK family tyrosine kinases as potential therapeutic targets for cancer

INTRODUCTION: The activated Cdc42-associated kinase (ACK) family, comprising TNK1 and ACK1/TNK2, are critical regulators of oncogenic signaling and epigenetic reprogramming. Their unique structural architecture, including ubiquitin-association domain, sterile alpha motif domain, and Mig6 homology regions, distinguishes them from other non-receptor kinases. ACK1 often, elevated in diverse malignancies, functions as a cytoplasmic transducer and nuclear epigenetic modifier, phosphorylating histones H4 at Tyr88 and H3 at Tyr54 driving cell survival, therapy resistance, and immune evasion. Conversely, TNK1 predominantly operates via ubiquitin‑mediated signaling, P activation, and STAT-dependent pathways in hematological cancers. Hence, understanding these mechanisms is crucial for developing targeted therapeutic strategies. AREAS COVERED: This review comprehensively examines the ACK family architecture, regulation, epigenetic mechanisms, and roles in several malignancies. It evaluates targeted therapies, immunotherapy, and drug development including selective inhibitors, dual agents, and rational combinations. EXPERT OPINION: The unique structure of ACK kinases presents a distinct therapeutic target for selective inhibition. ACK1/TNK2 and TNK1 offer complementary opportunities whose parallel clinical development is scientifically justified and strategically timely. Future research should map the complete ACK family epigenetic framework for biomarker‑driven selection and deeper mechanistic understanding. Clinical development of selective ACK inhibitors will potentially provide new treatment options for difficult-to-treat malignancies.