# Novel Mechanisms of MED12-TGFbeta-mediated resistance to PARP Inhibitors in BRCA-deficient Cancer Cells

> **NIH NIH F31** · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · 2022 · $33,410

## Abstract

Project Summary
This F31 application focuses on characterizing a novel resistance mechanism for PARP inhibitors. I am
requesting support for developing a project which I have previously initiated and published on. This proposal
addresses a fundamental gap in knowledge and could significantly impact cancer therapeutic strategies and
cancer patient survival. Moreover, the resources this application would provide would greatly impact my
development as a graduate student and independent scientist. This proposal would allow me the opportunity to
be exposed to state-of-the-art laboratory techniques including genomic sequencing and cryo-EM. This would
provide me with a complex mix of critical skills that will be important for my development into a well-rounded
scientist, and for which are highly attainable due to the support and resources provided by my mentorship team
and at Penn State College of Medicine.
In this proposal, I focus on elucidating the mechanisms by which MED12 and TGFb mediate resistance to PARP
inhibitors. I previously showed loss of MED12 confers resistance to PARP inhibitors in BRCA-deficient cells via
activation of the TGFb pathway. This resistance was underscored by an increase in homologous recombination
DNA repair efficiency and replication fork stability following TGFb pathway activation in BRCA-deficient cells.
Here, I hope to expand on this research to further define the mechanism behind this chemoresistance, to reduce
this gap in knowledge, and to gain experience and expertise in the rapidly growing field of structural oncology in
cancer research.
To investigate the role of MED12 and TGFb in chemoresistance further, I will explore three aims: 1) Investigate
specific interactions between MED12 with the Mediator complex and TGFbR2 and the impact of these
interactions on chemosensitivity in BRCA-deficient cells, 2) determine the role of ssDNA gap suppression in
MED12-TGFb-mediated chemoresistance and genomic stabilization, and 3) investigate the impact of TGFb
activation on the structure of mutant BRCA1 in patient-derived HCC1937 breast cancer cells. Achieving these
aims will expand my knowledge in the field of DNA damage and repair and expose me to cutting-edge new
techniques in the field of structural oncology. Thus, this work will advance my personal goals, and significantly
impact the field by providing new information on chemosensitivity in patients harboring BRCA-mutant cancers.

## Key facts

- **NIH application ID:** 10536964
- **Project number:** 1F31CA275340-01
- **Recipient organization:** PENNSYLVANIA STATE UNIV HERSHEY MED CTR
- **Principal Investigator:** Lindsey Marie Pale
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $33,410
- **Award type:** 1
- **Project period:** 2022-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10536964

## Citation

> US National Institutes of Health, RePORTER application 10536964, Novel Mechanisms of MED12-TGFbeta-mediated resistance to PARP Inhibitors in BRCA-deficient Cancer Cells (1F31CA275340-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10536964. Licensed CC0.

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