# Targeting cholesterol metabolism and replication stress response in cancer therapy

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2024 · $339,008

## Abstract

Project Summary:
Lung cancer is the leading cause of cancer deaths in both men and women. Non-small cell lung cancer (NSCLC)
accounts for large majority of lung cancer diagnoses, and novel treatment strategies for this disease are urgently
needed. ATR and its downstream effector CHK1 are key component of replication stress (RS) response that
specifically deal with the stalled replication forks during DNA replication and are critical for cell survival under
RS. Inhibitors targeting ATR and CHK1 are currently being tested in clinical trials. However, only limited efficacy
has been observed when those agents are combined with standard therapy. Identifying the new synergistic
conditions that render cells sensitive to ATR/CHK1 inhibitors will be key to improving the efficacy of these agents.
Squalene epoxidase (SQLE), an enzyme controlling cholesterol biosynthesis by converting squalene to
oxidosqualene in endoplasmic reticulum (ER), is frequently overexpressed in human cancers, including lung
cancer. High expression of SQLE is associated with poor prognosis. Our recent genome-wide loss of function
screen discovered that SQLE reduction led to enhanced sensitivity to a CHK1 inhibitor. Thus, the goal of this
application is to determine whether SQLE inhibition sensitizes NSCLC cells to ATR and CHK1 inhibitors and
whether high SQLE-expressing NSCLC cancer can be specifically targeted by the combined inhibition of SQLE
and ATR/CHK1. Our preliminary data suggest that SQLE inhibition by shRNA knockdown causes RS and
activates ATR/CHK1 activation. In addition, SQLE inhibition lead to increased protein expression of WIP1, a
phosphatase that suppress the activity of ATM, a master DNA damage response protein controlling DNA repair.
We hypothesize that SQLE inhibition leads to increased RS by suppressing DNA repair, rendering cells sensitive
to ATR and CHK1 inhibition. Thus, co-administration of an SQLE inhibitor and an ATR or CHK1 inhibitor could
synergistically suppress tumor growth. To test our hypothesis, three Specific Aims are proposed. Specific Aim 1
will interrogate the mechanism by which SQLE inhibition leads to increased WIP1 expression. Specific Aim 2 will
determine whether SQLE inhibition leads to increased RS by impairing DNA repair, particularly homologous
recombination, a major repair pathway that prevents and antagonizes RS. Specific Aim 3 will assess the efficacy
of combined SQLE inhibition and ATR/CHK1 inhibition in suppressing tumor cell growth using in vitro assays as
well as cell line-based and patient-derived xenograft (PDX) models of NSCLC. If successful, our studies will
reveal a new synthetic lethal interaction between inhibition of SQLE and ATR/CHK1 and will have a significant
impact on improving the survival of lung cancer patients by identifying novel therapeutic approaches.

## Key facts

- **NIH application ID:** 10789863
- **Project number:** 5R01CA249198-04
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Junran Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $339,008
- **Award type:** 5
- **Project period:** 2021-02-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10789863

## Citation

> US National Institutes of Health, RePORTER application 10789863, Targeting cholesterol metabolism and replication stress response in cancer therapy (5R01CA249198-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10789863. Licensed CC0.

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