ARKs beyond AMPK: LKB1-regulated kinases in cancer biology and therapy

Liver Kinase B1 (LKB1) is a master serine/threonine kinase that plays a pivotal role in cell metabolism, proliferation, polarity, and survival. Through the phosphorylation and activation of AMP-activated protein kinase (AMPK) and twelve AMPK-related kinases (ARKs), LKB1 controls complex signalling pathways that are frequently altered in cancer. Increasing evidence demonstrates that ARKs exert context-dependent functions, acting either as tumour suppressors or oncogenes depending on tissue type, genetic landscape, metabolic state and tumour microenvironment. This review provides a comprehensive overview of current knowledge on the structure, regulation, and biological functions of LKB1-activated ARKs, with particular emphasis on their involvement in metabolic reprogramming, cell cycle control, epithelial-mesenchymal transition, invasion, metastasis and cell death. We discuss how ARK deregulation contributes to tumour initiation and progression across multiple cancer types, while emphasizing three crucial aspects of ARK biology. First, we examine the molecular basis of their context-dependent tumour-suppressive or oncogenic functions discussing how these divergent roles influence tumour biology. Second, we summarize recent studies reporting how ARK signalling is rewired by LKB1 mutations, a still unexplored topic. Finally, we discuss emerging preclinical evidence on pharmacological inhibitors targeting specific ARKs, highlighting some therapeutic potential and major challenges that still limit their clinical translation. In particular, the lack of patient stratification based on ARK pathway status represent a major challenge to the successful implementation of ARK-targeted therapies. Given the complexity and tissue-specific behaviour of LKB1–ARK signalling network, a deeper mechanistic understanding is essential to exploit these kinases as therapeutic targets and develop more effective personalized cancer treatments. As key regulators of tumour progression, ARKs are rapidly emerging as promising candidates in precision oncology.