Integrative radiogenomic profiling of squamous cell lung cancer.

Cancer Res
Authors
Keywords
Abstract

Radiotherapy is one of the mainstays of anticancer treatment, but the relationship between the radiosensitivity of cancer cells and their genomic characteristics is still not well defined. Here, we report the development of a high-throughput platform for measuring radiation survival in vitro and its validation in comparison with conventional clonogenic radiation survival analysis. We combined results from this high-throughput assay with genomic parameters in cell lines from squamous cell lung carcinoma, which is standardly treated by radiotherapy, to identify parameters that predict radiation sensitivity. We showed that activation of NFE2L2, a frequent event in lung squamous cancers, confers radiation resistance. An expression-based, in silico screen nominated inhibitors of phosphoinositide 3-kinase (PI3K) as NFE2L2 antagonists. We showed that the selective PI3K inhibitor, NVP-BKM120, both decreased NRF2 protein levels and sensitized NFE2L2 or KEAP1-mutant cells to radiation. We then combined results from this high-throughput assay with single-sample gene set enrichment analysis of gene expression data. The resulting analysis identified pathways implicated in cell survival, genotoxic stress, detoxification, and innate and adaptive immunity as key correlates of radiation sensitivity. The integrative and high-throughput methods shown here for large-scale profiling of radiation survival and genomic features of solid-tumor-derived cell lines should facilitate tumor radiogenomics and the discovery of genotype-selective radiation sensitizers and protective agents.

Year of Publication
2013
Journal
Cancer Res
Volume
73
Issue
20
Pages
6289-98
Date Published
2013 Oct 15
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-13-1616
PubMed ID
23980093
PubMed Central ID
PMC3856255
Links
Grant list
RC2 CA148399 / CA / NCI NIH HHS / United States
R37 GM038627 / GM / NIGMS NIH HHS / United States
5T32CA009382-30 / CA / NCI NIH HHS / United States
R01 CA122794 / CA / NCI NIH HHS / United States
K08 CA163677 / CA / NCI NIH HHS / United States
R01 GM038627 / GM / NIGMS NIH HHS / United States
P01 CA154303 / CA / NCI NIH HHS / United States
R01 CA109038 / CA / NCI NIH HHS / United States
T32 CA009382 / CA / NCI NIH HHS / United States
RC2 CA138399-01 / CA / NCI NIH HHS / United States
Howard Hughes Medical Institute / United States
R01 CA140594 / CA / NCI NIH HHS / United States
GM38627 / GM / NIGMS NIH HHS / United States
R01 CA154480 / CA / NCI NIH HHS / United States
U54 CA112962 / CA / NCI NIH HHS / United States
R01 CA121941 / CA / NCI NIH HHS / United States