Annals of Oncology Advance Access originally published online on February 27, 2008
Annals of Oncology 2008 19(6):1053-1059; doi:10.1093/annonc/mdn006
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lung cancer |
EGFR regulation by microRNA in lung cancer: correlation with clinical response and survival to gefitinib and EGFR expression in cell lines
1 TGen Clinical Research Services at Scottsdale Healthcare, Scottsdale, AZ, USA
2 Department of Medical Oncology, University of Colorado Cancer Center, Aurora, CO, USA
3 Department of Surgery, Tokyo Medical University, Tokyo, Japan
4 Department of Pathology, University of Colorado at Denver and Health Sciences Center, Aurora, CO, USA
* Correspondence to: G. J. Weiss, MD, TGen Clinical Research Services at Scottsdale Healthcare, 10510 N 92nd Street, Suite 200, Scottsdale, AZ 85258, USA. Tel: +1-480-323-1350; Fax: +1-480-323-1359; E-mail: gweiss{at}tgen.org
Background: Allelic loss in chromosome 3p is one of the most frequent and earliest genetic events in lung carcinogenesis. We investigated if the loss of microRNA-128b, a microRNA located on chromosome 3p and a putative regulator of epidermal growth factor receptor (EGFR), correlated with response to targeted EGFR inhibition. Loss of microRNA-128b would be equivalent to losing a tumor suppressor gene because it would allow increased expression of EGFR.
Patients and Methods: We initially showed that microRNA-128b is a regulator of EGFR in non-small-cell lung cancer (NSCLC) cell lines. We tested microRNA-128b expression levels by quantitative RT–PCR, genomic copy number by quantitative PCR, and mutations in the mature microRNA-128b by sequencing. We determined whether microRNA-128b loss of heterozygosity (LOH) in 58 NSCLC patient samples correlated with response to gefitinib and evaluated EGFR expression and mutation status.
Results: We determined that microRNA-128b directly regulates EGFR. MicroRNA-128b LOH was frequent in tumor samples and correlated significantly with clinical response and survival following gefitinib. EGFR expression and mutation status did not correlate with survival outcome.
Conclusion: Identifying microRNA regulators of oncogenes could have far-reaching implications for lung cancer patients including improving patient selection for targeted agents, development of novel therapeutics, or development as early biomarkers of disease.
Key words: epidermal growth factor receptor, gefitinib, microRNA, non-small-cell lung cancer
Received for publication November 7, 2007. Revision received December 19, 2007. Accepted for publication January 2, 2008.
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