# Targeting TGFbeta/PDK4 to Overcome Drug Resistance in Colorectal Cancer

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2020 · $356,850

## Abstract

Abstract
 Colorectal cancer (CRC) is the second leading cause of cancer mortality in the USA.
The failure of treatment is due to resistance to chemotherapy, one of the biggest obstacles for
effective cancer therapy. Therefore, there is an urgent need to identify molecules or pathways
that can be targeted to overcome drug resistance and improve cancer treatment.
 TGFβ plays multiple functions including conferring drug resistance. However, the
mechanisms underlying TGFβ-mediated chemoresistance are not clear. PDK4 is one of the
isoforms of pyruvate dehydrogenase kinase (PDK), which phosphorylate pyruvate
dehydrogenase (PDH) and regulate glucose metabolism. We have discovered a novel function
of PDK4 that mediates the response of colon cancer cells to 5-FU treatment. We show that
PDK4, but not PDK 1-3, is differentially expressed in colon cancer cells, and that its expression
positively correlates with the resistance to 5-FU treatment. Knockdown of PDK4 sensitizes colon
cancer cells to 5-FU- or oxaliplatin-induced apoptosis. Experiments in tumor xenograft mouse
models demonstrate that knockdown of PDK4 increases the effectiveness of 5-FU-mediated
inhibition of tumor growth in vivo. Furthermore, for the first time, we have established a novel
crosstalk between TGFβ signaling and PDK4: TGFβ increases PDK4 expression while PDK4
enhances TGFβ signaling, which forms a positive feedback loop. Elevated PDK4 expression
contributes to TGFβ-mediated drug resistance in colon cancer cells. Studies of patient samples
indicate that expression of PDK4 and TGFβ signaling positively correlate with each other and
with chemoresistance in CRC. Therefore, our studies unveil an important function of
TGFβ/PDK4 in mediating drug resistance in CRC.
 In this proposal, we will determine the mechanism(s) underlying the crosstalk between
TGFβ signaling and PDK4, elucidate the mechanism(s) of PDK4-mediated drug resistance and
identify novel substrates of PDK4. We will determine the functional role of PDK4 in colon cancer
metastasis and the contribution of PDK4 and its crosstalk with TGFβ in CRC drug resistance
using an orthotopic mouse model. We will also demonstrate the clinical relevance in patient
samples. The completion of these studies will identify TGFβ/PDK4 as a novel regulator of
chemoresistance in CRC, substantially advance our understanding of molecular mechanisms
underlying drug resistance and provide proof-of-concept that combinations of 5-FU with
inhibitors of PDK4 or TGFβ could be potentially effective therapies to overcome
chemoresistance for CRC treatment.

## Key facts

- **NIH application ID:** 10000912
- **Project number:** 5R01CA212241-05
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Jing Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $356,850
- **Award type:** 5
- **Project period:** 2018-08-16 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10000912

## Citation

> US National Institutes of Health, RePORTER application 10000912, Targeting TGFbeta/PDK4 to Overcome Drug Resistance in Colorectal Cancer (5R01CA212241-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10000912. Licensed CC0.

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