# Sensitizing Ovarian Cancer To PARP inhibitor and platinum treatment

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2024 · $345,528

## Abstract

Abstract
 Homologous recombination (HR) is an important DNA repair mechanism for DNA damage
caused by PARPi and platinum. The HR pathway is closely associated with ovarian cancer
development and chemoresistance. Recent clinical studies showed that PARP inhibitors and
platinum are effective in treating ovarian cancers with mutations of BRCA1 or BRCA2, and other
genes encoding proteins involved in HR. Conversely, factors involved in HR promote the repair
of DNA lesions caused by PARP inhibitors and platinum, and this enhanced HR capability
contributes to chemotherapy resistance. Therefore, targeting HR pathway may be a powerful
strategy to overcome resistance to DNA damage-based therapy.
 Here we propose to study a new ATM-SYK-CtIP pathway that regulates HR. We found
the tyrosine kinase SYK plays an important role in HR. SYK’s function in immune regulation is
well established, however, its function in DNA repair has not been shown. We found that SYK
phosphorylates CtIP and regulates CtIP function in HR. SYK itself is also phosphorylated in an
ATM dependent manner and get recruited to the sites of DNA damage. Interestingly, SYK is
overexpressed in recurrent ovarian cancers; high expression of SYK is related to poor outcome
of OCs. Furthermore, inhibition of SYK in OC cell lines renders OC cells sensitize to PARPi or
cisplatin. Taken together, we hypothesize that the ATM-SYK-CtIP pathway is a new
regulatory mechanism for HR. Inhibiting of SYK sensitizes OC cells to cisplatin or PARPi,
suggesting SYK as the novel potential therapeutic targets or biomarkers for ovarian cancer
therapy. To test this hypothesis, we propose the following Specific Aims: 1. Investigate the
regulation of HR by SYK; 2. Investigate the regulation of SYK by the DNA damage signaling; 3.
Determine the inhibition of SYK in chemo-response in OCs using organoid and mouse models.
Our studies will reveal the novel function of SYK in DNA repair and response to chemotherapy.
In addition, it will reveal the new therapeutic targets and biomarkers in OC therapy.

## Key facts

- **NIH application ID:** 10860949
- **Project number:** 5R01CA264600-04
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Zhenkun Lou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $345,528
- **Award type:** 5
- **Project period:** 2021-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10860949

## Citation

> US National Institutes of Health, RePORTER application 10860949, Sensitizing Ovarian Cancer To PARP inhibitor and platinum treatment (5R01CA264600-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10860949. Licensed CC0.

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