# Energy reprogramming-regulated oncopathways and drug resistance in triple negative breast cancer

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $414,287

## Abstract

Abstract: Compared to other subtypes of breast cancers (BC), basal or triple negative (TN) BC suffers a poor
prognosis, caused by limited understanding of the driver signaling pathways. Thus, for TNBC, clinical benefit
from currently available targeted therapies is limited, and new therapeutic strategies are urgently needed. PI's
lab uses a research pipeline that utilizes transmitochondrial cybrid (cybrid) models. Cybrid system is an
excellent cell model that allows comparing mitochondria from different cells (example: benign and TNBC cells
with varying invasion/metastatic potential) in a common defined nuclear background. We apply multiple OMICs
approaches in cybrid models to discover mitochondria-nuclear communication and mitochondrial energy
reprogramming regulated cancer pathways. Using this research pipeline, we have recently published that
metastatic TNBC has high energy-dependence to mitochondrial fatty acid β-oxidation (FAO). We have also
discovered that FAO is a critical regulator of Src oncopathway in TNBC. We validated the findings from cybrid
models in parental BC cells, PDX models and clinical data. Proto-oncogene c-Src is one of the most
commonly upregulated cancer pathways in TNBC. However, multiple clinical trials including our own trial
showed only limited clinical benefit with single drug approach of Src inhibitors in unselected TNBC patients.
Thus, it is important to understand the mechanism of activation and drug resistance of c-Src in TNBC to
develop reliable treatment strategies to inhibit TNBC progression. N-myristoylation is a lipid modification with
the attachment of a fatty acid, myristate, onto the N- terminal glycine residue of target proteins. Our preliminary
analysis in cybrid models and parental cells suggest that FAO regulates myristoylation of c-Src by enhancing
cytosolic availability of myristoyl CoA. In this project we will validate this interesting finding using systematic
modulation of FAO pathway. Since frequent drug resistance occurs after Src inhibitor therapy in TNBC, we
have also analyzed the potential drug resistance mechanisms for FAO or Src inhibitor therapy in TNBC. Our
strong preliminary data suggest that drug resistance to FAO or Src inhibition is due to autophagy-mediated
tumor survival that is regulated by the reactive oxygen species (ROS)-induced MEK/ERK pathway. Thus, this
project will also validate this exciting mechanism using multiple research approaches. Considering our strong
in vitro and in vivo preliminary data, we have proposed large-scale preclinical studies using multiple PDX
TNBC models to determine benefit of combination drug strategy to overcome the resistance to FAO or Src
inhibition therapy in TNBC. Overall, this proposal is highly significant as it is expected to 1) reveal the
significance of mitochondrial crosstalk in the activation of Src signaling in TNBC and 2) develop strategies to
repurpose the existing FDA approved Src targeting drugs with suitable combination therapy for ...

## Key facts

- **NIH application ID:** 9833508
- **Project number:** 5R01CA234479-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Benny Abraham Kaipparettu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $414,287
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9833508

## Citation

> US National Institutes of Health, RePORTER application 9833508, Energy reprogramming-regulated oncopathways and drug resistance in triple negative breast cancer (5R01CA234479-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9833508. Licensed CC0.

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