# Reversing Resistance to PARP-Inhibitor in Triple Negative Breast Cancer

> **NIH NIH SC3** · HAMPTON UNIVERSITY · 2020 · $111,000

## Abstract

Of the several subtypes of breast cancer, the hormone-refractory `triple negative breast cancer (TNBC)'
(indicating lack of estrogen, progesterone and HER2neu receptor expression) are less responsive to
treatment and have a much worse prognosis as compared to receptor-positive breast cancer. The five-year
survival rate for TNBC is 77% versus 93% of women with other types of breast cancer. Poly (ADP-ribose)
polymerase (PARP) inhibitors (PARPi) are emerging as promising therapeutics for the treatment of TNBC in
a clinical setting. However, acquired resistance to PARPi presents a pervasive barrier to effective treatment
and the underlying mechanisms of resistance are poorly understood which has substantiated a need for
further investigation in the mechanisms of resistance to PARPi.
Autophagy is a self-digestive process, wherein in response to environmental stress, misfolded and
aggregated proteins are sequestered and delivered to the lysosome for subsequent degradation and
recycling. These recycled biomolecules resulting from autophagy, provide the rapidly growing tumor cells a
steady stream of nutrients. Many clinical studies have implemented an autophagy inhibitor (AI) in
combination with other drugs to elicit effective cell death in multiple cancers including breast cancer.
Autophagy inhibition has also shown to reverse the resistant phenotype of several cancers.
Perplexingly, while autophagy inhibition in combination with other chemotherapeutic agents has shown
promising therapeutic potential in TNBCs, no major advances have been made in understanding the
molecular mechanisms underlying autophagy in resistance to PARPi in TNBCs. Within the scope of this
proposal, we address an unmet pressing need to evaluate the synergistic effect of AI in combination with
PARPi in the reversal of TNBC resistance to PARPi. Current research proposal is aimed at improving our
understanding of the molecular mechanisms of autophagy-apoptosis crosstalk in conferring resistance to
PARPi in TNBC. Our main objectives are: 1) Using a combinatorial treatment of autophagy inhibitor (AI) with
PARPi, characterize the modulation of apoptotic and autophagic markers in cell death and 2) Identify and
evaluate the important rate-limiting factors such as LC3, Akt and oxidative stress involved in modulating
autophagy and apoptosis in the resistant TNBC model. The results and contributions of this study will be
significant and innovative as they can provide novel avenues for pharmacological intervention in
overcoming resistance to PARPi and change the treatment paradigm for this subset of breast cancer with
poor prognosis and limited treatment options.

## Key facts

- **NIH application ID:** 10004117
- **Project number:** 5SC3GM122655-04
- **Recipient organization:** HAMPTON UNIVERSITY
- **Principal Investigator:** Yogesh Kulkarni
- **Activity code:** SC3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $111,000
- **Award type:** 5
- **Project period:** 2017-09-11 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10004117

## Citation

> US National Institutes of Health, RePORTER application 10004117, Reversing Resistance to PARP-Inhibitor in Triple Negative Breast Cancer (5SC3GM122655-04). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10004117. Licensed CC0.

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