# Interruption of squalene epoxidase and DNA damage response in cancer therapy

> **NIH NIH R21** · OHIO STATE UNIVERSITY · 2020 · $218,790

## Abstract

Project Summary
Non-small cell lung cancer (NSCLC) is the most common lung cancer. Current treatments for this disease
remain inadequate, and novel treatment strategies are urgently needed. Squalene epoxidase (SQLE), an
enzyme controlling cholesterol biosynthesis by converting squalene to oxidosqualene, is frequently
overexpressed in NSCLC. High expression of this protein is associated with poor prognosis. Thus, the goal of
this application is to identify new approaches to treat high SQLE-expressing NSCLC. SQLE inhibitors are
currently used in clinic for treating fungal infection partially by accumulation of squalene. Strikingly, our recent
genome-wide loss-of-function screen and preliminary data suggest that SQLE inhibition by knockdown
enhanced the sensitivity to inhibitors targeting the DNA damage response (DDR) kinase CHK1 and its upstream
factor ATR. ATR-CHK1 axis are the key component of replication stress response. Inhibition of ATR and CHK1
leads to replication fork collapse and generation of DNA double strand breaks (DSBs), a major DNA structure
that can activate ATM kinase. Given the critical role of ATM in DSB repair and cell cycle checkpoints, the cells
with inhibited ATR/CHK1 activity rely heavily on ATM for survival. Our preliminary data suggest that SQLE
knockdown leads to an increase in WIP1, which is a phosphatase that suppresses ATM activity. Since it has
been reported previously that squalene accumulation lead to increase in WIP1 protein expression, we
hypothesize that SQLE inhibition suppresses ATM activity, thereby rendering the cells sensitive to ATR and
CHK1 inhibitors. Thus, a subset of NSCLC cells expressing high SQLE can be specifically targeted by the
combined inhibition of SQLE and ATR or CHK1. Two Specific Aims are proposed, which are to determine (1)
the mechanisms by which SQLE inhibition potentiates NSCLC cell sensitivity to ATR and CHK1 inhibitors and
(2) the synergistic antitumor efficacy of combined inhibition of SQLE and ATR or CHK1. In Aim 1, we will
determine whether SQLE inhibition suppresses ATM activity, thereby leading to impaired DDR, including DSB
repair and cell cycle checkpoint, in a manner dependent on WIP1 and squalene. An in vitro kinase assay, DSB
repair reporters, a cytogenetic assay and cell biological techniques will be used. To determine the involvement
of WIP1 and squalene, SQLE inhibition-induced defects in ATM activity and subsequent DDR will be evaluated
in cells expressing wild type and inactivated WIP1, and in cells with or without with squalene syntheses
inhibition. In Aim 2, we will assess the antitumor efficacy of the combined inhibition of SQLE and ATR or CHK1
using in vitro assays and cell line-based and patient-derived xenograft (PDX) models. If successful, our studies
will have a significant impact on improving the survival of lung cancer patients by identifying novel therapeutic
approaches from the perspective of simultaneously inhibiting the proteins required for cholesterol bio...

## Key facts

- **NIH application ID:** 9878345
- **Project number:** 1R21CA245590-01
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Junran Zhang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $218,790
- **Award type:** 1
- **Project period:** 2019-12-06 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9878345

## Citation

> US National Institutes of Health, RePORTER application 9878345, Interruption of squalene epoxidase and DNA damage response in cancer therapy (1R21CA245590-01). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9878345. Licensed CC0.

---

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