Maternal Embryonic Leucine Zipper Kinase (MELK) in Cancer: Biological Functions, Therapeutic Potential, and Controversies

The Maternal Embryonic Leucine Zipper Kinase (MELK) gene is a part of the Snf1/AMPK of serine/threonine kinase family. MELK has recently attracted considerable interest in the fields of stem cell and cancer biology. Furthermore, MELK is expressed normally during embryogenesis and in proliferative tissues; however, its aberrant overexpression has been observed in various malignancies, including glioma, breast, lung, colorectal, gastric, and hematological cancers. Higher MELK levels are often correlated with unfavorable prognosis, aggressive tumor manifestations, resistance to treatment, and stem-like tumor morphologies. Preclinical studies utilizing RNA interference and small-molecule inhibitors such as OTSSP167 demonstrate that MELK promotes cancer cell proliferation, survival, and metastasis. However, contrasting evidence from CRISPR/Cas9-based knockout studies indicates that MELK may not be essential for tumor growth, raising concerns that the observed anti-tumor effects of MELK inhibitors could partly result from off-target activity. This review aims to summarize the current understanding of MELK biology, including its functions in cell cycle regulation, apoptosis, oncogenic signaling pathways, and tumor stemness. In this review, we discuss the therapeutic potential and limitations of MELK inhibitors, the controversy regarding MELK dependency, and the implications for cancer diagnosis and treatment. MELK may not be a universal driver oncogene; nonetheless, it is consistently linked to aggressive disease, underscoring its potential as a prognostic biomarker and a candidate for therapeutic co-targeting in combination treatments.