# Synthetic lethality by targeting the core senescent mechanism in lung cancer.

> **NIH NIH R01** · DUKE UNIVERSITY · 2022 · $480,907

## Abstract

Abstract
Lung cancer is the most common cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC)
accounts for 85% of all lung cancer cases and is generally diagnosed at advanced stages, requiring multimodal
therapy involving radiation, chemotherapy, and targeted therapies. Despite these medical interventions, the five-
year survival rates of NSCLC patients are less than 5%, highlighting the need for innovative and more effective
strategies to treat NSCLC. Dysregulation of cyclin-dependent kinases (CDKs), such as CDK4 and CDK6, occurs
in 70% of NSCLC patients and results in aberrant cellular proliferation and tumorigenesis. Palbociclib (PD-03329,
trade name Ibrance) is the first cyclin dependent kinase 4 and 6 inhibitor to be approved for breast cancer and
is currently investigated as a monotherapy for other solid tumors, including NSCLC. While palbociclib has shown
initial improvements in progression-free survival in a phase II clinical trial for recurrent or metastatic NSCLC
patients, over half of patients either experience adverse effects or develop resistance and disease progression
after eight weeks of treatment. Palbociclib achieves its therapeutic effect by arresting cells in G1 phase and
promoting an irreversible cell cycle arrest known as cellular senescence. Senescence was initially thought to
suppress tumorigenesis; however, growing evidence has suggested that senescent cells can paradoxically
promote tumorigenesis and cancer relapse by altering the surrounding tumor microenvironment. The use of
senolytic therapies to promote synthetic lethality may bypass the negative side effects of senescence and
enhance the efficacy of palbociclib by either driving palbociclib-treated cells towards apoptosis rather than
senescence. Through genetic screening, we identified thrombomodulin (THBD), a potent anticoagulant
endothelial receptor, as a novel senolytic target for palbociclib-induced senescence. THBD-mediated signaling
was upregulated during palbociclib-induced senescence in NSCLC cancer cell lines and served as a critical
regulator of NSCLC cell fate and survival, as inhibition of THBD signaling in NSCLC cells attenuated senescence
and promoted apoptosis. Importantly, inhibiting the activity of THBD downstream signaling by an FDA-approved
drug caused senescent NSCLC cells to apoptose under treatment of palbociclib. Built on these findings, we
propose two specific aims to fully investigate the mechanism by which THBD signaling mediates the senescent
program induced by palbociclib and validate this pathway as a target to induce synthetic lethality in palbociclib-
treated NSCLC cells both in vitro and in vivo for combinational therapy with the ultimate goal to develop
preclinical and clinical trials to improve overall NSCLC patient outcome.

## Key facts

- **NIH application ID:** 10368019
- **Project number:** 5R01CA244564-03
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** XIAO-FAN WANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $480,907
- **Award type:** 5
- **Project period:** 2020-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10368019

## Citation

> US National Institutes of Health, RePORTER application 10368019, Synthetic lethality by targeting the core senescent mechanism in lung cancer. (5R01CA244564-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10368019. Licensed CC0.

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