# POLQ Synthetic Lethality in HR-Deficient Pancreatic Adenocarcinoma

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $700,147

## Abstract

Pancreatic ductal adenocarcinoma (PDA) is a highly lethal human malignancy, typically diagnosed at an
advanced stage and known to be largely unresponsive to chemotherapy and ionizing radiation. Recent genomic
characterization of PDA reveals that between 20-25 % of PDA harbor recurrent mutations in genes, including
BRCA1/2, PALB2, and ATM, which are critical for homologous recombination (HR), an important form of DNA
repair. In many patients, these may be germline mutations. This subgroup of PDAs, termed HR-deficient PDA,
has emerged as a defined biological entity associated with increased chemoresistance and a more aggressive
disease course.
 The defects in HR observed in these tumors impart cells with a specific vulnerability to PARP inhibitors and
platinum-containing therapy. Still, as observed in the case of many other targeted therapies, only a fraction of
HR-defective patient tumors respond to PARP inhibition. More so, many patients that initially respond
eventually often develop resistance and progress. Therefore, novel therapies which can be effective against HR-
defective PDA, alone or in combination with PARP inhibitors or other combinatorial regimens, are urgently
needed.
 We have recently determined that inactivation of the HR pathway is associated with overexpression of
polymerase theta (PolƟ, also known as POLQ) in PDA. POLQ is a key enzyme that regulates an alternative
pathway of DNA repair, known as the alternative non-homologous end-joining (Alt-NHEJ) pathway. Data from
our group indicates that in the setting of defective HR, Alt-NHEJ becomes a critical pathway responsible for the
repair of DNA breaks. Furthermore, we show that POLQ inhibition in HR-defective tumor cells demonstrates a
synthetic lethality phenotype, not observed in cells with intact HR. In this proposal, we present exciting new data
that knockdown of POLQ is synthetically lethal in PDA cells deficient for Brca1, Brca2, Atm, and Palb2 genes.
POLQ knockdown significantly inhibited growth of both Brca2- and Atm-deficient tumors cells in vivo. Further,
POLQ knockdown significantly upregulated the cGAS-STING pathway in HR-deficient PDA and promoted T cell
infiltration.
 Here, we plan to examine the unique role of POLQ in pancreatic cancer biology and its role as a novel
therapeutic target in HR-defective pancreatic cancers. We will also evaluate the antitumor effect of combining
POLQ inhibition with: i) current standard cytotoxic chemotherapies, ii) PARP inhibition, and iii)
immunotherapy. An important goal of this proposal is to generate a set of data for proof-of-concept that
targeting POLQ in a valuable therapeutic strategy in HR-defective pancreatic cancer, as POLQ inhibitors are
currently in development for clinical use.

## Key facts

- **NIH application ID:** 10051163
- **Project number:** 1R01CA245005-01A1
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** DIANE M SIMEONE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $700,147
- **Award type:** 1
- **Project period:** 2020-07-16 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10051163

## Citation

> US National Institutes of Health, RePORTER application 10051163, POLQ Synthetic Lethality in HR-Deficient Pancreatic Adenocarcinoma (1R01CA245005-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10051163. Licensed CC0.

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