# Molecular mechanism and preclinical development of BETi and PARPi combination therapy

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $360,922

## Abstract

PROJECT SUMMARY
Although poly (ADP-ribose) polymerase inhibitor (PARPi) has emerged as a promising drug for patients with
cancer, primary and acquired resistance is a major clinical problem for PARPi in cancer treatment. Several drug
combination strategies have been designed and evaluated in preclinical and early clinical trials to overcome this
challenge. Therefore, strategies to enhance response to PARPi in primary and acquired homologous
recombination (HR)-proficient tumors would represent a significant advance in cancer care. Bromodomains and
extra-terminal domain inhibitor (BETi) has been rapidly advanced into early clinical trials and has shown
impressive anti-tumor activity. Given that clinical activity of BETi alone may be insufficient to manage patients
according to recent clinical trials, the combination of BETi with other treatment methods need to be designed
and evaluated. Using a drug synergistic screen that combined a PARPi with 20 well-characterized epigenetic
drugs, we identified BETi as a drug that acted synergistically with PARPi in HR-proficient cancer cells. Functional
assays demonstrated that repressed BET activity reduces HR and subsequently enhances PARPi-induced DNA
damage in cancer cells. Chemical inhibition or genetic depletion of BET proteins impairs transcription of several
essential genes in HR. Moreover, BETi treatment sensitized tumors to PARP inhibition in preclinical animal
models of HR-proficient breast and ovarian cancers. Finally, we showed that the BRD4 gene was significantly
and focally amplified across common adult cancers, although its gene fusion was a rare genomic alteration.
Thus, we hypothesize that BETi may suppress HR and enhance NHEJ, thereby sensitizing HR-proficient cancer
cells to PARP inhibition. Aim 1. Characterize the molecular mechanisms by which BETi synergistically acts with
PARPi. Aim 2. Evaluate the combination therapy of BET and PARP inhibitors in preclinical models. Aim 3. Define
immune responses to BETi and PARPi treatment in the tumor microenvironment. Our proposed studies may
provide strong rationale for clinical application of PARPi in the setting of combination with BETi to treat both
cancers with de novo resistance to PARPi therapy and cancers with acquired resistance. Therefore, combination
with BETi could greatly expand the utility of PARP inhibition to patients with HR-proficient cancer.

## Key facts

- **NIH application ID:** 10328490
- **Project number:** 5R01CA225929-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Lin Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $360,922
- **Award type:** 5
- **Project period:** 2019-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10328490

## Citation

> US National Institutes of Health, RePORTER application 10328490, Molecular mechanism and preclinical development of BETi and PARPi combination therapy (5R01CA225929-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10328490. Licensed CC0.

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