# A multi-scale analysis of the mutagenicity of cisplatin and its modulation of acquired chemoresistance in high-grade serous ovarian cancer

> **NIH NIH F31** · UNIVERSITY OF TEXAS AT AUSTIN · 2021 · $36,611

## Abstract

PROJECT SUMMARY.
High-grade serous ovarian cancer (HGSOC) accounts for up to 80% of ovarian cancer deaths, due to
recurrence in over half of patients associated with platinum-based chemoresistance. Intratumor heterogeneity
(ITH) is thought to be the main contributor in resistance. ITH permits diverse phenotypic landscapes among
cells that may provide certain clones advantages in resisting or tolerating chemotherapy. Cisplatin, routinely
used in HGSOC treatment, forms platinum-DNA (Pt-DNA) adducts as its main cytotoxic mechanism. However,
Pt-DNA adducts are mutagenic, particularly due to the misincorporation of incorrect nucleotides by DNA
polymerases β (polβ) and η (polη) opposite these adducts. Despite evidence that polβ, polη, and the bypass of
Pt-DNA adducts play roles in cisplatin resistance, the molecular mechanisms that govern this mutagenic
bypass are unclear. In addition, HGSOC is characterized by vast genome instability that causes intratumor
genetic diversity and augments the possibilities for the acquisition of resistance. As one of the most mutagenic
drugs, cisplatin further increases this genetic diversity and induces unwanted mutations that may elicit the
emergence of de novo resistant clones. I hypothesize that polβ and polη execute the mutagenic events of
cisplatin, and the mutagenicity of cisplatin modulates the de novo origination of resistant clones that propagate
resistance in HGSOC. This proposal seeks to define the molecular mechanisms that enable the mutagenic
bypass of Pt-DNA adducts, and in conjunction, determine how the mutagenicity of cisplatin modulates the
acquisition of HGSOC resistance during cisplatin treatment. Recent lineage tracing through DNA barcoding
technologies have enabled exciting quantitative analyses of subclonal architecture throughout treatment of
cancer populations. However, subsequent analyses destroy barcoded cellular samples, limiting further studies.
COLBERT enables both lineage tracing and isolation through lineage-specific gene expression of a fluorescent
reporter. I will employ COLBERT in an unprecedented longitudinal study of de novo resistance that emerges
throughout cisplatin treatment of HGSOC cell line populations. This proposal will perform gene expression and
whole genome sequencing analyses of individual de novo resistant lineages throughout treatment to determine
key de novo mutations that confer resistance, and understand how resistant lineages came to acquire
resistance over time. The 2015 Ovarian Cancer Action meeting described the need for studies that aim to
better understand clonal diversity and genome instability contributing to acquired HGSOC resistance. This
work will address this by uniquely uniting molecular and systems level approaches to provide characterizations
of cisplatin’s mutagenicity. This study will provide a holistic understanding of how cisplatin fails to act solely as
a cytotoxic drug and induces undesirable mutagenic events, and how these de novo mutations may...

## Key facts

- **NIH application ID:** 10048638
- **Project number:** 5F31CA243349-02
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** Caroline Kate Vilas
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $36,611
- **Award type:** 5
- **Project period:** 2020-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10048638

## Citation

> US National Institutes of Health, RePORTER application 10048638, A multi-scale analysis of the mutagenicity of cisplatin and its modulation of acquired chemoresistance in high-grade serous ovarian cancer (5F31CA243349-02). Retrieved via AI Analytics 2026-05-30 from https://api.ai-analytics.org/grant/nih/10048638. Licensed CC0.

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