# Overcoming chemoresistance in triple negative breast cancer

> **NIH NIH R01** · UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA · 2022 · $92,543

## Abstract

PROJECT SUMMARY
Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype. It accounts for ~15% of
all breast cancer patients yet is responsible for 30% of breast cancer deaths. TNBC is treated primarily by
conventional chemotherapy; however, resistance to therapy is common leading to high mortality rates.
Recently, we identified hypoxia-induced ECM re-modeler, lysyl oxidase (LOX) as a key mediator of
doxorubicin resistance in TNBC (Saatci et al, Nature Communications, 2020). LOX inhibition offers a unique
opportunity to re-sensitize the most aggressive breast tumors to standard-of-care chemotherapeutics. The
overall objectives of this project are to (i) delineate the roles of LOX in chemoresistance, (ii) determine the
mechanisms through which LOX exerts these roles, (iii) and generate prototypes of potent and selective LOX
inhibitors to overcome chemoresistance in TNBC. We hypothesize that (i) LOX induces resistance not only
to doxorubicin but also to other chemotherapeutic drugs by its enzymatic activity; (ii) LOX exerts this effect
both by increasing collagen cross-linking/fibronectin assembly (canonical LOX function) leading to reduced
drug penetration and increased integrin-mediated signaling and by regulating transcription (non-canonical
LOX function) via interacting and oxidizing its substrates, culminating in activation of FAK/Src signaling and
cell survival; and (iii) targeting LOX activity with selective small-molecule inhibitors will overcome
chemoresistance by blocking both canonical and non-canonical LOX functions in TNBC. These hypotheses
will be tested by pursuing three specific aims: 1) To determine the role of canonical ECM cross-linking function
of LOX in resistance to different chemotherapeutics in TNBC. We will test the general chemosensitizer role
of LOX and necessity of its enzymatic activity by generating cells with CRISPR-mediated LOX knock-out and
reconstitution and testing their effects on chemoresistance in vitro and in vivo. LOX-mediated ECM changes
will be analyzed by advanced microscopy techniques, e.g. MP-SHG, and the resulting drug penetration will
be studied by IF and MALDI-MSI. 2) To determine the role of non-canonical transcription-regulating functions
of LOX in TNBC chemoresistance. We will determine if LOX controls global transcription and identify novel
LOX substrates by combining transcriptomics (RNA-Seq) and proteomics (TurboID) approaches. We will
generate oxidation-deficient LOX substrates and test their effects on LOX-mediated chemoresistance. 3) To
characterize novel LOX enzymatic inhibitors and test their potential as chemosensitizers in TNBC. We will
test the selectivity of our inhibitors in cells with LOX knock-out/reconstitution and their off-target profiles and
test their chemosensitization ability in organoids. We will perform PK/PD and toxicity profiling studies and
test the inhibitors for overcoming chemoresistance in TNBC PDXs. The proposed project is expected to
provide...

## Key facts

- **NIH application ID:** 10345694
- **Project number:** 1R01CA267101-01
- **Recipient organization:** UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
- **Principal Investigator:** Ozgur Sahin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $92,543
- **Award type:** 1
- **Project period:** 2021-12-16 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10345694

## Citation

> US National Institutes of Health, RePORTER application 10345694, Overcoming chemoresistance in triple negative breast cancer (1R01CA267101-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10345694. Licensed CC0.

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