# CHEK2 loss promotes prostate cancer resistance to PARP inhibitors

> **NIH NIH R21** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $251,048

## Abstract

ABSTRACT
 Metastatic castration-resistant prostate cancer (mCRPC) is an incurable disease that is expected to
account for approximately 33,000 deaths each year in the United States. Therapeutic options are limited for
mCRPC patients that extend life. There is an urgent need for developing novel targeted therapies, especially
personalized therapies based on genomic alterations in tumors. Recent genomic studies have revealed a
variety of actionable molecular targets with underlying genomic alterations. Notably, alterations in genes
involved in DNA damage response are among the most common genetic events and enriched in mCRPC.
These alterations have been correlated with particular therapeutic vulnerabilities in prostate cancer (PCa) cells.
Specifically, defects in homologous recombination (HR) repair would predict sensitivity to inhibition of Poly
(ADP-ribose) polymerase (PARP). PARP inhibitors (PARPis) are a new type of targeted therapy, which works
by preventing the enzyme PARP from repairing damaged DNA in tumor cells. The BRCA1 and BRCA2 genes
encode proteins essential for HR repair. Cancer cells lacking BRCA1/2 depend instead on PARP-regulated
DNA repair and are highly sensitive to PARPis. The U.S. FDA has approved two PARP inhibitors (olaparib and
rucaparib) for the treatment of mCRPC patients with deleterious BRCA1/2 or HR repair gene mutations.
 One of the major barriers to effective treatment using PARPis is how to select patients who most likely
benefit from PARP inhibition. Resistance to PARPis also represents a formidable clinical problem. Through
genome-wide CRISPR (clustered regularly interspaced short palindromic repeats) screens, we recently
discovered a number of genes that mediate cellular response and resistance to PARP inhibition. Unexpectedly,
we found that loss of CHEK2 (Checkpoint kinase 2), a cell cycle checkpoint regulator and tumor suppressor
gene, significantly increased PCa cell resistance (instead of sensitivity) to PARP inhibition. CHEK2 plays a role
in HR repair and CHEK2 alterations are currently used to predict olaparib response in the FDA-approved HR
repair gene panel. The goal of this project is to determine to what extent loss of CHEK2 renders PCa cells
resistant to PARP inhibition and define the underlying mechanisms in preclinical PCa models. At completion of
this project, we expect to demonstrate that CHEK2 loss is a biomarker to predict PARPi resistance. The
findings from this study may change patient eligibility for PARP inhibition and have a positive impact on future
clinical practice.

## Key facts

- **NIH application ID:** 10512381
- **Project number:** 1R21CA267496-01A1
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Li Jia
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $251,048
- **Award type:** 1
- **Project period:** 2022-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10512381

## Citation

> US National Institutes of Health, RePORTER application 10512381, CHEK2 loss promotes prostate cancer resistance to PARP inhibitors (1R21CA267496-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10512381. Licensed CC0.

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