# Targeting DNA repair in KRAS mutated lung cancer by chemical screening

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $491,730

## Abstract

Targeting DNA repair in KRAS mutated lung cancer by chemical screening
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specific aims, study design, and relevance to the cancer problem. You will prepare the abstract as a separate file when you
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Background: Lung cancer is the leading cause of cancer death in the US. Around 30% lung
adenocarcinoma carries KRAS mutation, which lacks targeted therapies. Chemotherapy remains
the mainstay treatment for KRAS mutated lung cancers. Many chemotherapy kills cancer cells by
causing massive DNA damage, particularly double strand breaks (DSBs). However, cells also
evolved protective mechanisms (DNA damage response and repair) to evade the cell killing effect
of chemotherapy. Hence, small molecules that inhibit DNA damage response and DSB repair can
be repurposed into effective chemo-sensitizers for KRAS mutated lung cancers.
Preliminary Data: Natural products display a wide variety of structural complexity and diversity,
representing a rich resource for drug discovery. To identify chemo-sensitizers for KRAS mutated
lung cancer, we screened a natural product library (~1000 compounds with various structural
types) and identified cardiac glycosides as potent DNA damage response inhibitors. We demonstrate
that cardiac glycosides specifically inhibit the 5' to 3' DSB end resection, a process that is required for
the activation of DNA damage response and faithful DSB repair. Cardiac glycosides strongly
enhanced the growth inhibition effect of DSB-inducing drugs on KRAS mutant lung cancer cells
while having much less effect on normal lung fibroblasts, indicating a cancer specific effect of these
compounds. This therapy sensitizing effect was confirmed in xenografted lung cancers in mice.
Objective: The goal of this project is to determine the molecular targets and detailed mechanisms by
which cardiac glycosides sensitize chemotherapy in KRAS mutated lung cancers.
Study Design: In Aim 1, we will determine how cardiac glycosides inhibit the 5' to 3' DSB end
resection. DSB end resection is controlled by many proteins including 53BP1, BRCA1, UHRF1,
etc. We hypothesize that cardiac glycosides inhibit DSB end resection by regulating expression
levels of these critical DSB genes. Through whole genome sequencing and stable isotope labeling
with amino acids (SILAC), we identified UHRF1 as the top candidate as UHRF1 plays a critical role
in promoting the 5' to 3' end resection of DSBs and inhibition of UHRF1 suppresses DSB end
resection. Here we will determine (1) how UHRF1 mediates DNA damage response and DSB
repair in the presence of cardiac glycosides, and (2) the molecular details by which cardiac
glycosides regulate the expression level of UHR...

## Key facts

- **NIH application ID:** 9954071
- **Project number:** 5R01CA230453-02
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** You-Wei Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $491,730
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9954071

## Citation

> US National Institutes of Health, RePORTER application 9954071, Targeting DNA repair in KRAS mutated lung cancer by chemical screening (5R01CA230453-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9954071. Licensed CC0.

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