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

## TL;DR

MELK is a kinase overexpressed in many cancers, linked to aggressive behavior and treatment resistance, but its role as a universal driver is debated.

## Contribution

The paper reviews MELK's biological functions, therapeutic potential, and controversies, proposing it as a conditional oncogenic vulnerability.

## Key findings

- MELK overexpression correlates with poor prognosis and aggressive cancer traits.
- MELK inhibitors show promise but have limitations and context-specific effects.
- MELK may be a conditional vulnerability in p53-deficient TNBC and glioma stem cells.

## Abstract

MELK is a serine/threonine kinase that regulates cell cycle progression, proliferation, apoptosis, migration, and stemness. MELK is overexpressed in many solid and hematologic malignancies. Furthermore, high MELK levels correlate with aggressive disease, poor survival, treatment resistance, and cancer stem-like features. Several small-molecule inhibitors and RNAi-targeting MELK have suppressed the development and progression of various cancers. OTSSP167 has shown promising results in phase I and II clinical trials. However, a study employing CRISPR/Cas9 knockout in breast cancer cell lines reported that loss of MELK did not impair proliferation. The review concludes that MELK is a robust prognostic biomarker of proliferation and aggressive behavior across multiple cancers but is not a universal driver of tumor growth. Discrepancies may arise from off-target effects of RNAi or inhibitors, context differences across cancer types, and differences in study settings. MELK is proposed as a conditional oncogenic vulnerability, especially in p53-deficient triple-negative breast cancer (TNBC) and glioma stem cells. Further research is needed to clarify the target selectivity of inhibitors, context-specific dependencies, and the optimal use of MELK-focused agents in combination therapies rather than as standalone treatments.

The Maternal Embryonic Leucine Zipper Kinase (MELK) gene is a member of the Snf1/AMPK serine/threonine kinase family. MELK has recently attracted considerable interest in cancer biology due to its aberrant overexpression in various malignancies, including glioma, breast, lung, colorectal, gastric, and hematological cancers. It has been shown that higher MELK levels are often correlated with unfavorable prognosis, aggressive tumor manifestations, resistance to treatment, and stem-like tumor morphologies. In this review we aim to summarize the current understanding of MELK biology, including its functions in cell cycle regulation, apoptosis, oncogenic signaling pathways, and tumor stemness. We also discuss the therapeutic potential, limitations, and controversy of MELK inhibitors, and implications in 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.