# Mechanism of lung cancer resistance to tyrosine kinase inhibitor and radiation treatments

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2021 · $616,835

## Abstract

Lung cancer is the leading cause of cancer mortality worldwide. Abnormal oncogenic
activation of EGFR signaling is one of major driver molecules for triggering lung cancer, small
molecule tyrosine kinase inhibitors (TKI) have provided benefit for lung cancer patients, and
radiation treatments are commonly used to improve the patient outcome. Recent studies from
our laboratories show that oxidative stress and altered miRNA expression are important in
therapeutic responses to radiation and chemotherapy. Our preliminary results demonstrate that
persistent p70S6K1 activation and oxidative stress play an important role in resistant lung
cancer cells upon TKI and radiation treatments, but not in sensitive cells. We also showed
higher expression levels of NOX4 and EZH2 in the resistant cells that are resistant to TKI and
radiation treatments. We hypothesize that p70S6K1 is induced by NOX4 and EZH2
overexpression, and miR-152 suppression and MDM2 are key downstream effectors for
regulating lung cancer development and therapeutic resistance to targeted therapy and
radiation treatment. We plan to test this hypothesis through three aims. Aim 1 is to determine
role and mechanism of p70S6K1 in therapeutic resistance to TKI-targeted therapy and radiation
treatment, and to identify p70S6K1 upstream regulators and downstream effectors for
transmitting signal(s) for the treatment resistance. Aim 2 is to determine whether p70S6K1
induces lung tumor growth and TKI-targeted therapeutic resistance through MDM2 and miR-152
suppression using a lung orthotopic tumor model; and to determine whether p70S6K1 and
NOX4 are required for tumor development using human lung cancer Patient-Derived Tumor
(PDX) model. Aim 3 is to investigate whether levels of p70S6K1, NOX4, MDM2, and/or miR-152
are correlated with TKI-targeted therapy responses in lung cancer cohort; and are correlated
with human lung cancer stages and survival; and to determine whether p70S6K1 regulates
tumor angiogenesis through VEGF using a humanized chimeric tumor model. This R01 proposal
will help to understand divergent resistant mechanisms in response to EGFR-TKI and radiation
therapy. The successful completion of proposal will provide better understanding of lung cancer
resistant mechanism and potential novel therapeutic option for lung cancer treatment in the
future.

## Key facts

- **NIH application ID:** 10207544
- **Project number:** 5R01CA232587-05
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Ling-Zhi Liu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $616,835
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10207544

## Citation

> US National Institutes of Health, RePORTER application 10207544, Mechanism of lung cancer resistance to tyrosine kinase inhibitor and radiation treatments (5R01CA232587-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10207544. Licensed CC0.

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