Abazeed, Mohamed E., Adams, Drew J., Hurov, Kristen, Tamayo, Pablo, Creighton, Chad J., Sonkin, Dmitriy, Giacomelli, Andrew O., Pashtan, Itai, Du, Charles, Fries, Daniel F., Wong, Kwok-Kin, Mesirov, Jill P., Loeffler, Jay S., Schreiber, Stuart L., Hammerman, Peter S. and Meyerson, Matthew (2013) Integrative radiogenomic profiling of squamous cell lung cancer. Cancer Research, 73 (20). pp. 6289-6298. ISSN 0008-5472.CAN-13-1616

Abstract

Radiation therapy is one of the mainstays of anti-cancer treatment, but the relationship between the radiosensitivity of cancer cells and their genomic characteristics is not well defined. Here we report the development of a high-throughput platform for measuring radiation survival in vitro and its validation by comparison to 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 radiation therapy, to identify parameters that predict radiation sensitivity. We confirmed that activation of NFE2L2, a frequent event in lung squamous cancers, correlates with radiation resistance. NFE2L2 knockdown conferred both growth arrest and radiation sensitivity in a cell line with NFE2L2 mutation but not in a wild type cell line. An expression-based, in silico screen nominated inhibitors of 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. To assess determinants of radiation sensitivity further, we combined results from this high-throughput assay with single-sample gene set enrichment analysis (ssGSEA) 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, high-throughput approach 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 radiation sensitizers and protective agents.

Item Type:	Article
Date Deposited:	13 Oct 2015 13:13
Last Modified:	13 Oct 2015 13:13
URI:	https://oak.novartis.com/id/eprint/9451