# Metabolic adaptation in residual triple negative breast cancer following chemotherapy

> **NIH NIH R37** · BAYLOR COLLEGE OF MEDICINE · 2024 · $401,438

## Abstract

ABSTRACT
Oxidative phosphorylation (oxphos), a mitochondrial energy generation process, promotes chemotherapeutic
resistance in breast and other cancers. In fact, transplantation of mitochondria from tumorigenic cells into non-
tumorigenic cells demonstrated these organelles are necessary and sufficient for aggressive phenotypes of triple
negative breast cancer (TNBC) cells. Nearly 50% of TNBC patients treated with neoadjuvant (pre-surgical)
chemotherapy (NACT; combined anthracyclines, platinums, and/or taxanes) will harbor substantial residual
tumor burden, leading to extremely high risk of recurrence and death4. There are no approved targeted therapies
for neoadjuvant treatment of non-BRCA-mutant TNBC. Thus, there is an urgent need to find ways to eradicate
residual tumor cells. Furthermore, the mechanisms driving metabolic reprogramming in chemoresistant TNBC
are unclear. Our comparisons of serial pre- and post-NACT patient-derived xenograft (PDX) and human TNBC
biopsies revealed heightened oxphos signatures in residual tumor cells, and we demonstrated oxphos is a
unique therapeutic vulnerability of residual TNBC. We observe significantly higher protein levels of the
mitochondrial fusion-driving GTPase optic atrophy 1 (OPA1) in post- vs. pre-NACT TNBC biopsies. Furthermore,
high expression of mitochondrial fusion-driving proteins in breast cancer is associated with poor survival. The
impact of mitochondrial structure, dictated by the balance of mitochondrial fission and fusion, on metabolism
varies highly across tumor types. Despite the importance of mitochondria to metabolism, no studies have
addressed how mitochondrial structure impacts metabolic states driving TNBC therapeutic responses. Our
preliminary data provide evidence that NACT increases mitochondrial fusion and metabolism in vitro and in vivo.
We can increase oxphos and NACT resistance in TNBC cells by genetically or pharmacologically perturbing
mitochondrial fission with Mdivi-1, a Drp1 inhibitor. Conversely, perturbation of mitochondrial fusion with
MYLS22, an OPA1 inhibitor, decreased oxphos and NACT resistance. We hypothesize OPA1-driven
mitochondrial fusion mediates an NACT-induced metabolic switch to promote chemoresistance in TNBC cells.
To address this, our specific aims are to: 1) Determine if mitochondrial fusion is responsible for chemotherapy-
induced oxphos in TNBC, and 2) Target and quantify mitochondrial fusion in residual TNBC mouse models and
serial patient biopsies. These results will increase our mechanistic understanding of regulation of the
mitochondrial life, as well as mechanisms driving metabolic adaptations in TNBC. Furthermore, our findings will
provide additional metabolic therapeutic targets to overcome chemoresistance in residual TNBCs.

## Key facts

- **NIH application ID:** 10757746
- **Project number:** 5R37CA269783-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Gloria Vittone Echeverria
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $401,438
- **Award type:** 5
- **Project period:** 2022-12-27 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10757746

## Citation

> US National Institutes of Health, RePORTER application 10757746, Metabolic adaptation in residual triple negative breast cancer following chemotherapy (5R37CA269783-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10757746. Licensed CC0.

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