EGFR regulation by microRNA in lung cancer: correlation with clinical response and survival to gefitinib and EGFR expression in cell lines.
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.


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.


CONCLUSIONS
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.
Weiss
G J
GJ
TGen Clinical Research Services at Scottsdale Healthcare, Scottsdale, AZ, USA. gweiss@tgen.org
Bemis
L T
LT
Nakajima
E
E
Sugita
M
M
Birks
D K
DK
Robinson
W A
WA
Varella-Garcia
M
M
Bunn
P A
PA
Haney
J
J
Helfrich
B A
BA
Kato
H
H
Hirsch
F R
FR
Franklin
W A
WA
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D045744:Cell Line, Tumor; D000077156:Gefitinib; D015870:Gene Expression; D018773:Genes, erbB-1 / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D035683:MicroRNAs; D011799:Quinazolines / Q000627:therapeutic use*; D016019:Survival Analysis
D000970:Antineoplastic Agents; D035683:MicroRNAs; D011799:Quinazolines; D000077156:Gefitinib