# Investigating the effect of ERCC2 mutations on DNA repair capacity and chemo-radiotherapy response in muscle-invasive bladder cancer

> **NIH NIH K08** · DANA-FARBER CANCER INST · 2021 · $176,947

## Abstract

Project Summary
 Muscle-invasive bladder cancers (MIBCs) represent an aggressive subset of bladder tumors that are
associated with high mortality rates despite intensive multimodality treatment. DNA-damaging agents like
cisplatin play a key role in the treatment of MIBC and many other solid tumors, yet validated biomarkers of
response to DNA-damaging therapy are lacking.
 Recently, an association between somatic mutations in ERCC2, a core member of the nucleotide
excision repair (NER) pathway, and improved response to cisplatin-based chemotherapy was uncovered in
MIBC, representing one of the first validated examples of an association between a tumor DNA repair pathway
alteration and response to a DNA-damaging agent. Preliminary functional analysis suggests that the observed
ERCC2 mutations result in loss of NER capacity; however, the functional underpinnings of this association
across tumors and clinical contexts are not known. This proposal aims to characterize the role of mutations in
ERCC2 and other DNA repair genes in MIBC biology and treatment response.
 One of the limitations to understanding the biological relevance of novel DNA repair alterations in
tumors is the lack of robust, efficient assays to test the functional effects of observed mutations. The first aim
of this application will employ a novel high-throughout, fluorescence-based microscopy assay to measure the
ability of ERCC2 mutations to support cellular NER. The assay will be applied to all ERCC2 mutations
observed across several MIBC cohorts, and findings will be interpreted in the context of available treatment
response and patient outcome data in order to define the functional landscape of ERCC2 mutations and
develop a framework for predicting functional effects and therapeutic implications of ERCC2 mutations.
 Although MIBCs harboring ERCC2 mutations have improved response to cisplatin-based
chemotherapy, the mechanism by which heterozygous ERCC2 mutations confer sensitivity is not known. The
second aim will utilize a combination of cellular and biochemical approaches to dissect the effect of mutations
on ERCC2 protein function, cellular properties, and sensitivity to established and emerging MIBC therapies. In
addition, the effect of ERCC2 mutations on tumorigenesis will be investigated by introducing ERCC2 mutations
into a normal human urothelial cell line alone and in combination with other known MIBC driver mutations.
 The third aim will investigate the hypothesis that mutations in ERCC2 (or other DNA repair genes)
define a subset of MIBC patients who are ideal candidates for bladder-preserving treatment with concurrent
cisplatin-based chemoradiotherapy (CRT). Targeted sequencing of ERCC2 and 1000 additional cancer genes
will be performed in two large cohorts of MIBC patients treated using CRT. These analyses are likely to further
define a role for ERCC2 as a biomarker in MIBC and may have broad implications for understanding the role of
DNA repair pathway alterations ...

## Key facts

- **NIH application ID:** 10201523
- **Project number:** 5K08CA219504-05
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Kent W Mouw
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $176,947
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10201523

## Citation

> US National Institutes of Health, RePORTER application 10201523, Investigating the effect of ERCC2 mutations on DNA repair capacity and chemo-radiotherapy response in muscle-invasive bladder cancer (5K08CA219504-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10201523. Licensed CC0.

---

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