# Validation of OXPHOS gene amplification as a driver of hypoxia and treatment resistance in NSCLC

> **NIH NIH R03** · OHIO STATE UNIVERSITY · 2024 · $78,750

## Abstract

ABSTRACT
Non-small cell lung cancer (NSCLC) is a highly aggressive disease typically diagnosed at locally advanced or
metastatic stage, with dismal prognosis associated with high rates of treatment resistance and disease
recurrence. Clinical management of NSCLC varies according to the stage. High-dose stereotactic body radiation
therapy (SBRT) is the standard of care for localized non-resectable NSCLC. However, as discovered more than
six decades ago, tumor hypoxia is a significant barrier to effective radiation therapy. In the last decade, first line
NSCLC treatment has been substantially reinforced with the introduction of immunotherapy targeting immune
checkpoints such as programmed cell death 1 (PD-1), yet long-term disease control occurs in less than 25% of
NSCLC patients. Therefore, understanding the mechanisms of the treatment resistance is essential to address
the dire need of introducing novel synergistic therapies to elicit enhanced treatment response in hypoxic NSCLC
tumors. Tumor hypoxia has been associated with anti-cancer treatment resistance for decades, yet its role in
clinical management of NSCLC remains largely unexplored. The basis of tumor hypoxia has traditionally been
attributed to the oxygen supply deficit as malformed tumor vasculature fails to meet the high demand of the
rapidly proliferating tumor mass. However, our preliminary analysis of NSCLC patient datasets in the Cancer
Genome Atlas (TCGA) PanCancer dataset revealed a significant correlation between high-level expression of
nuclear genes encoding mitochondrial subunits essential for oxidative phosphorylation (OXPHOS), and high-
level expression of hypoxia-regulated genes (Buffa hypoxia score). Furthermore, we have observed a direct
positive correlation between high frequency of copy number amplification (CNA) of several essential OXPHOS
genes, and hypoxia levels in NSCLC patient samples. Because mitochondrial function consumes up to 90% of
available cellular oxygen, its activity may be indirectly regulating oxygen availability in the tumor
microenvironment by rapidly consuming oxygen upon its delivery to the tumor. Mechanistically, this leads to the
hypothesis that OXPHOS gene amplification drives mitochondrial function which may, in turn, promote tumor
hypoxia and treatment resistance in NSCLC. The proposed R03 validation study therefore aims to identify the
role of high frequency of OXPHOS gene CNA in driving tumor hypoxia and treatment resistance of NSCLC
tumors. Upon completion, this study will contribute to current understanding of mechanisms of refractory disease
in NSCLC patients and may provide novel markers of treatment outcome.

## Key facts

- **NIH application ID:** 10873131
- **Project number:** 5R03CA280489-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Martin Benej
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $78,750
- **Award type:** 5
- **Project period:** 2023-06-21 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10873131

## Citation

> US National Institutes of Health, RePORTER application 10873131, Validation of OXPHOS gene amplification as a driver of hypoxia and treatment resistance in NSCLC (5R03CA280489-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10873131. Licensed CC0.

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