# Interruption of cholesterol metabolism and replication stress response in cancer therapy

> **NIH NIH R21** · OHIO STATE UNIVERSITY · 2020 · $401,115

## Abstract

Project Summary: Lung cancer is the most common malignancy worldwide, both in incidence and mortality.
Unfortunately, this disease is often driven by activating oncogenes that are either not amenable to direct
therapeutic intervention or when targeted therapies are available treatment resistance invariably develops, thus
highlighting the urgent need for the development of novel treatment strategies. Metabolic reprogramming is a
hallmark of cancer and is a pharmaceutical target for cancer therapy. SQLE, a key enzyme required for
cholesterol synthesis, is frequently overexpressed in lung cancer and is associated with poor prognosis.
Excitingly, our recent genome-wide loss of function screen discovered that SQLE reduction caused enhanced
sensitivity to an inhibitor targeting CHK1, a key DNA damage response (DDR)/replication stress (RS) response
protein that is required for cell survival and proliferation under RS. Our preliminary data suggest that SQLE
inhibition by shRNA knockdown causes RS and activates ATR/CHK1 signaling. Thus, the goal of this
application is to determine whether high SQLE-expressing lung cancer can be specifically targeted by the
combined inhibition of SQLE and CHK1 or its upstream factor ATR. Because the inhibition of proteins required
for cholesterol biosynthesis leads to decreased dNTP and increased reactive oxygen species (ROS) (i.e., two
common mechanisms for RS ), we hypothesize that SQLE inhibition leads to increased RS by deregulation of
dNTP and/or ROS, triggering the ATR/CHK1 axis for survival. Thus, co-administration of an SQLE inhibitor and
an ATR or CHK1 inhibitor could synergistically suppress tumor growth of lung cancer. Specific Aim 1 will
delineate whether SQLE inhibition-induced RS is associated with perturbation of the dNTP pool and increased
ROS, using liquid chromatography-tandem mass spectrometry, DNA fiber assays and biochemical/cell
biological approaches. Specific Aim 2 will assess the antitumor effects of the combined inhibition of SQLE and
RS response proteins using in vitro assays and cell line-based and patient-derived xenograft (PDX) mouse
models of lung cancer. If successful, our studies will have a significant impact on improving the survival of lung
cancer patients by identifying novel therapeutic approaches.

## Key facts

- **NIH application ID:** 10044013
- **Project number:** 1R21CA241242-01A1
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Junran Zhang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $401,115
- **Award type:** 1
- **Project period:** 2020-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10044013

## Citation

> US National Institutes of Health, RePORTER application 10044013, Interruption of cholesterol metabolism and replication stress response in cancer therapy (1R21CA241242-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10044013. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*