# Targeting MARK2-HDAC signaling to overcome paclitaxel resistance in pancreatic cancer

> **NIH NIH U54** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2024 · $247,902

## Abstract

Abstract Text
Many antitubulin agents, such as paclitaxel (Taxol), have been used extensively for treatment of several types
of cancer, including breast, ovarian, lung, and pancreatic cancers. Despite their wide use in cancer treatment,
however, patient response is highly variable and drug resistance remains a major clinical issue. It is therefore
essential to identify prognostic markers to predict the patient response and to enhance drug sensitivity.
Through biochemical and cell-based kinome-wide screens, we identified MARK2 (microtubule affinity-
regulating kinase 2) as a critical regulator for Taxol chemosensitivity in PDAC (pancreatic ductal
adenocarcinoma) cells. We show that MARK2 is phosphorylated in response to antitubulin chemotherapeutics.
We further identified the corresponding kinase and mapped phosphorylation sites. MARK2 determines Taxol
cytotoxicity in PDAC cells without affecting growth under normal conditions. Mechanistically, our findings also
suggest that MARK2 controls Taxol chemosensitivity by regulating class IIa HDACs (histone deacetylase).
MARK2 directly phosphorylates HDAC4 upon Taxol treatment. MARK2-phosphorylated HDAC4 positively
regulates YAP (yes-associated protein) activity and controls expression of YAP target genes specifically
induced by Taxol. Inhibition of HDACs sensitizes PDAC cells to Taxol treatment in vitro and in
immunocompetent animals. Our hypothesis is that the MARK2-HDACs axis functions as a therapeutic target
for overcoming Taxol resistance in PDAC patients. We will test our central hypothesis by three specific aims.
Aim 1: Determine the role and regulation of MARK2 in response to antitubulin chemotherapeutics; Aim 2:
Elucidate the downstream effectors and mechanisms of MARK2 in response to Taxol chemotherapeutics; Aim
3: Targeting HDACs and serine metabolism to overcome Taxol resistance in PDAC. The identification of new
regulators and/or signaling pathways triggered by antitubulin drugs will shed light on the mechanisms
underlying chemoresistance. Our study suggests that combining HDAC inhibitors with antitubulin agents (e.g.
Taxol) will have enhanced efficacy in treatment of drug-resistant and/or recurrent PDAC patients.

## Key facts

- **NIH application ID:** 10926948
- **Project number:** 5U54CA274329-03
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** Jixin Dong
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $247,902
- **Award type:** 5
- **Project period:** 2022-09-20 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10926948

## Citation

> US National Institutes of Health, RePORTER application 10926948, Targeting MARK2-HDAC signaling to overcome paclitaxel resistance in pancreatic cancer (5U54CA274329-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10926948. Licensed CC0.

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