# Rational Combination Therapy with PARP Inhibitors in Triple Negative Breast Cancer

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $425,403

## Abstract

Triple negative breast cancer (TNBC) is one subtype of breast cancer that frequently relapses and
leads to worse outcome than patients with hormone receptor-positive subtypes. PARP is currently the
most promising drug target for TNBC, and multiple PARP inhibitors (PARPi) have been developed and
tested in clinical trials. Although PARPi show higher response rate in patients carrying BRCA mutations,
there are still high percentage of BRCA mutations carried patients does not respond to PARPi. Thus,
developing strategies to make PARPi treatment more effective and to identify biomarkers to stratify
patients is critical. Our recent publication in Nature Medicine (2016) showed that in response to reactive
oxygen species, c-Met interacts with and phosphorylates PARP1 at Y907. Moreover, we demonstrated
that c-Met-mediated phosphorylation is critical for PARPi resistance, and that c-Met inhibitors sensitize
TNBC cells to PARPi. The long-term goal of our research is to develop the effective therapeutic
strategies for TNBC. To this end, we will seek the novel biomarkers and treatment strategies to improve
the efficacy of PARPi. We hypothesized that PARP1 protein is regulated by its phosphorylation, and
that phosphorylation status of PARP1 and the expression of the corresponding kinases that
phosphorylate PARP1 will serve as appropriate biomarkers for combinational treatment. Multiple
kinases can phosphorylate the same substrates, resulting in signal crosstalk. Also, TNBC is a
heterogeneous disease, and the distinct kinases play an important role in different TNBC. Therefore,
we also hypothesize that similar to c-Met, other protein kinases also have functions to regulate PARP1
activity through phosphorylation in TNBC. Potential molecules we will study are EGFR, which also
directly interacts with PARP1 and phosphorylate it. We will investigate the role of these kinases in
PARP1 regulation and PARPi resistance. Thus, we propose the following three aims; Aim 1. To
systematically validate the significance of c-Met–mediated phosphorylation in PARPi resistance in
mouse models and TNBC patient samples; Aim 2. To determine the role of EGFR-mediated PARP
phosphorylation in PARPi resistance in TNBC; Aim 3. To determine the role of c-Met and EGFR
interplay in PARPi resistance in TNBC. If our proposal is successful, several phosphorylation sites in
PARP1 can be used as biomarkers to guide the combinational treatment of PARPi and correlated
kinase inhibitors. We will particularly focus on c-Met and EGFR because inhibitors of these kinases are
currently used in the clinic or in clinical trials, allowing for faster progression of our biomarker-guided
rationale combination therapy into clinical trials.

## Key facts

- **NIH application ID:** 10229578
- **Project number:** 5R01CA211615-05
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Liuqing Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $425,403
- **Award type:** 5
- **Project period:** 2017-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10229578

## Citation

> US National Institutes of Health, RePORTER application 10229578, Rational Combination Therapy with PARP Inhibitors in Triple Negative Breast Cancer (5R01CA211615-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10229578. Licensed CC0.

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