# The roles of anti-apoptotic proteins BCL-XL and MCL1 in mediating survival of high-grade serous ovarian cancer following drug-induced DNA damage

> **NIH NIH K08** · DANA-FARBER CANCER INST · 2022 · $184,711

## Abstract

PROJECT SUMMARY/ABSTRACT
High-grade serous ovarian cancer (HGSOC) is often diagnosed at an advanced stage and has a poor prognosis.
Although many patients initially respond to platinum and paclitaxel chemotherapy, most patients develop
recurrent disease that is resistant to chemotherapy. Chemotherapy resistance is an unmet therapeutic need in
HGSOC. To address this challenge, Dr. Stover performed systematic functional genomic screens to identify
mediators of platinum and paclitaxel resistance. Anti-apoptotic proteins that protect cells from apoptotic cell death
were strongly associated with chemotherapy resistance. Conversely, targeted drugs that inhibit anti-apoptotic
proteins BCL-XL and MCL1 sensitized HGSOC cells to chemotherapy. In this proposal, Dr. Stover will test the
hypothesis that BCL-XL and MCL1 are key mediators of HGSOC survival following chemotherapy-induced DNA
damage. Aim 1 will determine whether BCL-XL and MCL1 inhibitors increase apoptosis when combined with
DNA-damaging chemotherapy in HGSOC cell lines and patient cells, and explore effects of DNA-damaging
agents on BCL-XL and MCL1 interactions with pro-apoptotic proteins. Aim 2 will assess whether the DNA
damage repair capacity of HGSOC cells affects their dependency upon BCL-XL and MCL1 for survival. A
chemical screen will aim to identify DNA-damaging agents and other drugs that synergize with BCL-XL and
MCL1 inhibitors to kill HGSOC cells. Aim 3 will evaluate the role of BCL-XL and MCL1 in the survival of
chemotherapy-resistant HGSOC. Combinations of BCL-XL and MCL1 inhibitors and chemotherapy will be tested
in HGSOC cell lines with empiric platinum resistance in vitro, and HGSOC cell-line xenografts and patient-derived
xenografts in vivo. Finally, we will use genomic and proteomic approaches to analyze patient samples of
untreated and chemotherapy-resistant HGSOC for changes in BCL-XL and MCL1 and related anti-apoptotic
proteins, as well as other chemotherapy resistance pathways. In summary, this study will assess the requirement
for BCL-XL and MCL1 in HGSOC chemotherapy resistance, and begin to elucidate the crosstalk between
apoptosis and DNA damage repair pathways in resistance. Combinations of BCL-XL or MCL1 inhibitors with
DNA-damaging agents may be effective therapies for HGSOC. Dr. Stover's long-term goal is to contribute to
new treatment options for patients with ovarian cancer through independent research focusing on ovarian cancer
biology, genomics, and therapeutics. The pursuit of this goal will be facilitated by the outstanding institutional
environment of the Dana-Farber Cancer Institute and accomplished mentors, including Drs. Matthew Meyerson,
MD PhD and Anthony Letai, MD PhD. Collaborations with the Broad Institute will contribute exceptional
resources for clinical genomics and chemical screening, and an expert advisory committee will provide guidance
on experimental design and career advancement. A research training program, including courses and mentoring
...

## Key facts

- **NIH application ID:** 10443783
- **Project number:** 5K08CA237871-04
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Elizabeth Harmon Stover
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $184,711
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10443783

## Citation

> US National Institutes of Health, RePORTER application 10443783, The roles of anti-apoptotic proteins BCL-XL and MCL1 in mediating survival of high-grade serous ovarian cancer following drug-induced DNA damage (5K08CA237871-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10443783. Licensed CC0.

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