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Radiother Oncol. 2013 Sep;108(3):440-445. doi: 10.1016/j.radonc.2013.06.020. Epub 2013 Jul 25.

High NOTCH activity induces radiation resistance in non small cell lung cancer.

Author information

1
Department of Radiation Oncology (MAASTRO Lab), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center (MUMC+).
2
Department of Radiation Oncology, Radboud University Medical Center, Nijmegen.
3
Department of Pathology, Maastricht University Medical Center (MUMC+).
4
Department of Pulmonary Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.
#
Contributed equally

Abstract

BACKGROUND AND PURPOSE:

Patients with advanced NSCLC have survival rates <15%. The NOTCH pathway plays an important role during lung development and physiology but is often deregulated in lung cancer, making it a potential therapeutic target. We investigated NOTCH signaling in NSCLC and hypothesized that high NOTCH activity contributes to radiation resistance.

MATERIALS AND METHODS:

NOTCH signaling in NSCLC patient samples was investigated using quantitative RT-PCR. H460 NSCLC cells with either high or blocked NOTCH activity were generated and their radiation sensitivity monitored using clonogenic assays. In vivo, xenograft tumors were irradiated and response assessed using growth delay. Microenvironmental parameters were analyzed by immunohistochemistry.

RESULTS:

Patients with high NOTCH activity in tumors showed significantly worse disease-free survival. In vitro, NOTCH activity did not affect the proliferation or intrinsic radiosensitivity of NSCLC cells. In contrast, xenografts with blocked NOTCH activity grew slower than wild type tumors. Tumors with high NOTCH activity grew significantly faster, were more hypoxic and showed a radioresistant phenotype.

CONCLUSIONS:

We demonstrate an important role for NOTCH in tumor growth and correlate high NOTCH activity with poor prognosis and radioresistance. Blocking NOTCH activity in NSCLC might be a promising intervention to improve outcome after radiotherapy.

KEYWORDS:

Hypoxia; NOTCH; NSCLC; Radiation

PMID:
23891097
PMCID:
PMC4948666
DOI:
10.1016/j.radonc.2013.06.020
[Indexed for MEDLINE]
Free PMC Article

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