# Dissecting and Targeting MAST1 Signaling in chemoresistant Cancers

> **NIH NIH R01** · EMORY UNIVERSITY · 2024 · $434,313

## Abstract

PROJECT SUMMARY
 Platinum drugs such as cisplatin serve as a mainstay of cancer therapy, but resistance limits their curative
potential. Through a kinome-wide RNAi screen, we identified microtubule-associated serine/threonine kinase 1
(MAST1) as a main cisplatin resistance driver in human cancers and identified lestaurtinib as a promising MAST1
inhibitor. MAST1 was found to reactivate the MEK1 pathway, conferring cisplatin resistance. However, we do
not know how this pivotal factor, MAST1, is activated, expressed, and associated with oncogenic mutations.
 Through a proteomics study and mutational analysis, we identified aurora kinase B (AURKB) as an upstream
kinase that phosphorylates MAST1 at S1258, critical for MAST1 activation. Our transcription factor study
revealed that the transcription factor CEBPb is responsible for MAST1 gene expression, and wildtype p53 inhibits
the activity of CEBPb to induce MAST1. In line with this observation, TCGA analysis revealed that MAST1
expression is high in lung cancer patients with mutant p53. These data suggest that AURKB and p53/CEBPb
may regulate MAST1 in transcription-independent and -dependent manners.
 Recently, cancer has been indicated as a metabolic disease and altered unique metabolic properties of
cancer cells make cancer metabolism an attractive target in treating cancers. However, the link between MAST1
and cellular metabolism has never been explored. Through real-time cell metabolic analysis and metabolomic
profiling, we found that MAST1 elevates glucose uptake and controls redox metabolism when cells are exposed
to cisplatin. We noticed that MAST1 is involved in the gene induction of glucose transporter 1 (GLUT1) and
peroxiredoxin 2 (PRX2). Furthermore, MAST1 directly phosphorylates c-myc at S62 and may stabilize c-myc,
the potential transcription regulator of GLUT1 and PRX2. These preliminary data suggest that MAST1 may play
a critical role in the metabolic reprogramming of cancer cells. To further benefit from the MAST1 therapy, we
performed a kinase inhibitor synergy screen and identified the combination of lestaurtinib and ponatinib as an
optimal combinatorial strategy to overcome cisplatin resistance. Moreover, lestaurtinib with BAY-876 (GLUT1
inhibitor) synergistically enhanced cisplatin sensitivity in various cancer cells.
 Our central hypothesis is that MAST1 modulated by AURKB and CEBPb provides metabolic advantages for
cancer cells to confer cisplatin resistance; MAST1 signaling axis linked to AURKB/CEBPb and GLUT1/PRX2
represents a promising cisplatin-sensitizing target. Three specific aims are proposed: (1) To determine how
MAST1 is regulated by AURKB and p53/CEBPb; (2) To decipher the mechanism of how MAST1-c-myc-GLUT1
and PRX2 signaling confers metabolic advantages; (3) To evaluate the optimal MAST1-based combinatorial
strategy in treating cisplatin-resistant cancers.

## Key facts

- **NIH application ID:** 10999650
- **Project number:** 1R01CA287782-01A1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Sumin Kang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $434,313
- **Award type:** 1
- **Project period:** 2024-07-17 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10999650

## Citation

> US National Institutes of Health, RePORTER application 10999650, Dissecting and Targeting MAST1 Signaling in chemoresistant Cancers (1R01CA287782-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10999650. Licensed CC0.

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