# Understanding and targeting MELK overexpression in breast cancer cells

> **NIH NIH R15** · UNIVERSITY OF TOLEDO · 2020 · $468,255

## Abstract

PROJECT SUMMARY
 Maternal Embryonic Leucine Zipper Kinase (MELK) is listed among clinically used Mammaprint and Prosigna
(PAM50) breast cancer signature genes. MELK overexpression has also been reported in other cancers and
cancer stem cells. These studies suggested that MELK overexpression predicts poor survival of cancer patients.
A small molecule MELK inhibitor OTS167 is currently tested in Phase I clinical trials. However, recent results
questioned the specificity of MELK inhibitors, and CRISPR/Cas9 mediated MELK knockout suggested MELK is
not an essential kinase for cell proliferation. This has posed a paradox: why then is MELK overexpressed in
cancer cells? There is clearly knowledge gap and clinical urgency to better delineate MELK functions. Particularly,
we still lack the understanding about MELK action at the individual cell level. Based on literature survey and
preliminary data, we propose the central hypothesis that MELK regulates cell cortex stability during late mitosis
and controls cell division symmetry. The hypothesis leads to the conceptual innovation that MELK
overexpression might not affect proliferation of the mass of cancer cells, but could still exert functional
significance through amplifying cancer stem cells by engaging symmetric cell division. The protein level,
phosphorylation level and kinase activity of MELK all peak during mitosis. Previously we have identified MELK
as a gene co-expressing with core centromere/kinetochore proteins. MELK is also a top-ranking chromosomal
instability (CIN) signature gene. We reason that MELK does have some functions during mitosis, and in proper
contexts its mitotic activities may impact cell fates. Stem cells including cancer stem cells normally go through
asymmetric cell division. However, in certain situations stem cells also divide symmetrically to increase the pool
of stem cells. The central hypothesis will be tested in three specific aims. Aim 1. To elucidate the spatio-
temporal control of MELK activity during mitosis; Aim 2. To test whether MELK amplifies cancer stem
cells by regulating cell division symmetry; Aim 3. To assess surrogate markers for MELK inhibition. The
project is expected to bridge mechanistic insights into MELK cell biology and its known overexpression in breast
cancers. The project is expected to identify at least one urgently needed surrogate marker to evaluate the efficacy
of MELK inhibition in cells. It will be collaborated with several experts and will become a perfect training platform
for undergraduate and graduate students in the Department of Biological Sciences at the University of Toledo.

## Key facts

- **NIH application ID:** 9880902
- **Project number:** 1R15CA238894-01A1
- **Recipient organization:** UNIVERSITY OF TOLEDO
- **Principal Investigator:** Song-Tao Liu
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $468,255
- **Award type:** 1
- **Project period:** 2019-12-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9880902

## Citation

> US National Institutes of Health, RePORTER application 9880902, Understanding and targeting MELK overexpression in breast cancer cells (1R15CA238894-01A1). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9880902. Licensed CC0.

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