# Characterizing the XRN1 exoribonuclease as a therapeutic target in non-small cell lung cancer

> **NIH NIH K08** · DANA-FARBER CANCER INST · 2024 · $208,829

## Abstract

PROJECT SUMMARY/ABSTRACT
Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality worldwide. The development
of targeted molecular therapies that inhibit mutant oncogenic proteins and immunotherapies that inhibit the PD-
1/PD-L1 pathway have improved outcomes for subsets of patients with NSCLC. However, targeted therapies
are only effective against NSCLCs that harbor actionable genetic alterations. In addition, anti-PD-1/PD-L1
immune checkpoint inhibitors are most effective against NSCLCs that express high levels of PD-L1 or have a
high tumor mutation burden. Thus, patients with NSCLCs that lack these features do not benefit from targeted
therapies and are less likely to benefit from immunotherapies, emphasizing the need to identify novel therapeutic
targets in this disease. This project seeks to characterize the XRN1 exoribonuclease, which functions in cellular
RNA degradation, as a target that may have broad therapeutic potential in NSCLC. My preliminary data show
that XRN1 inactivation induces cell lethality in a subset of human NSCLC cell lines. In an implantable mouse
tumor model, XRN1 deletion can synergize with anti-PD-1 immunotherapy to enhance tumor eradication. Aim 1
will define the molecular signaling pathways that mediate cell lethality after XRN1 deletion in a subset of human
NSCLC cell lines. Aim 2 will assess the impact of XRN1 deletion in mouse NSCLC models of anti-PD-1
immunotherapy. Aim 3 will determine whether XRN1 gene expression in human NSCLC tumors may serve as a
predictive biomarker for treatment response to anti-PD-1 immunotherapy. The long-term goals of the proposed
research are to gain fundamental insights into how RNA metabolism regulates cancer cell survival and anti-
tumor immunity and to establish RNA metabolism pathways as potential therapeutic targets in NSCLC.
The applicant, Dr. Tao Zou, is an oncologist at Dana-Farber Cancer Institute (DFCI). He spends 80% of his time
engaged in research and career development activities and 20% of his time in clinical practice caring for patients
with lung cancer. Dr. Zou has outlined a five-year career development plan that will enable him to achieve his
goal of leading an independent laboratory that conducts basic and translational research at the intersection of
RNA biology and lung cancer immunotherapy. Dr. Zou will perform the proposed research under the mentorship
of Dr. Matthew Meyerson, an expert in lung cancer biology with a strong record of training independent
investigators in academic cancer research. Together with expert members of Dr. Zou’s Scientific Advisory
Committee, Dr. Meyerson will ensure that Dr. Zou will obtain additional training in innate immune RNA sensing,
tumor immunology, translational studies using human biospecimens, and computational biology. Dr. Zou will
conduct the proposed research primarily at DFCI and will leverage additional resources available to him at the
Broad Institute and Harvard Medical School. DFCI is a rich...

## Key facts

- **NIH application ID:** 10879043
- **Project number:** 5K08CA252169-04
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Tao Zou
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $208,829
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10879043

## Citation

> US National Institutes of Health, RePORTER application 10879043, Characterizing the XRN1 exoribonuclease as a therapeutic target in non-small cell lung cancer (5K08CA252169-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10879043. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*