# B55 alpha deficiency as a therapeutic target in cancer

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2020 · $369,660

## Abstract

PROJECT SUMMARY
Ovarian cancer is the 5th leading cause of cancer death in women. The overall 5-year survival rate for epithelial
ovarian cancer (EOC), the most common type, remains approximately 30% over the last several decades. High-
grade serous ovarian cancer (HGSOC) is the most common and lethal form of EOC. Thus, the novel strategies
for treating HGSOC are urgently needed. Cancer cells often carry genetic defects that provide opportunities for
specific targeting. Expression of the B55 α, a regulatory subunit of the heterotrimeric serine/threonine
phosphatase PP2A, is reduced in 46% of ovarian cancers, as a result of loss of heterozygosity. Our recent novel
genome-wide synthetic lethality screen discovered that B55 α reduction led to the enhanced sensitivity of cells
to an inhibitor targeting replication stress response kinase CHK1. Currently, inhibitors of CHK1 and its upstream
effector ATR are being tested in clinical trials without precise guidance of biomarkers to identify responsive
populations, which significantly reduce the efficacy of these agents. Thus, the goal of this application is to
establish the molecular basis for targeting B55 α defective HGSOC by ATR/CHK1 inhibitors and for B55 α being
a biomarker to guide the use of those agents. PP2A has diverse functions, including the negative regulation of
numerous oncogenic signaling. Oncogene activation can cause replication stress that could be lethal to the cells.
ATR/CHK1 signaling suppresses replication stress to less toxic levels. Thus, cancer cells with increased
replication stress, such as cancer cells with c-Myc activation/expression, heavily rely on ATR/CHK1 for survival.
Given the role of PP2A in negatively regulating multiple oncogenic pathways, B55 α deficiency may lead to
oncogene activation and replication stress, rendering these cells sensitive to ATR/CHK1 inhibition. We
hypothesize that ATR and CHK1 inhibitors specifically target B55 α-defective HGSOC cells by enhancing
replication stress. Thus, reduced B55 α expression could be a biomarker to guide the use of ATR and CHK1
inhibitors. Three Specific Aims are proposed. In Aim 1, we will determine the role of c-Myc in B55 α deficiency-
induced replication stress. In Aim 2, we will determine the causes of the B55 α deficiency-induced replication
stress. In Aim 3, we will assess the anti-tumor activities of ATR and CHK1 inhibition in targeting B55 α defective
HGSOC cells. If successful, our study will have a significant impact on improving the survival of ovarian cancer
patients by identifying new treatment approaches and by providing a new stratification biomarker for identifying
ATR/CHK1 inhibitor sensitive populations.

## Key facts

- **NIH application ID:** 9981116
- **Project number:** 1R01CA240374-01A1
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Junran Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $369,660
- **Award type:** 1
- **Project period:** 2020-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9981116

## Citation

> US National Institutes of Health, RePORTER application 9981116, B55 alpha deficiency as a therapeutic target in cancer (1R01CA240374-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9981116. Licensed CC0.

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