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Researchers ID Distinct Genetics in Never-Smokers' Lung Cancer

NEW YORK (GenomeWeb News) – A microRNA called miR-21 is often over-expressed in lung cancer tumors from never-smokers, suggesting these patients may eventually benefit from treatments targeting the miRNA or other components of the same pathway.

While comparing tumors from lung cancer patients who smoked with those who hadn't, researchers from the National Cancer Institute and elsewhere saw that the number and type of mutations present in the tumors differed between the two groups, as did the microRNA profiles. Although smokers had more DNA mutations and aberrantly regulated miRNAs overall, never-smokers tended to have more mutations in the epidermal growth factor receptor, EGFR, and enhanced expression of miR-21.

That suggests that smokers and never-smokers may develop lung cancer through a different pathway — and may respond to different types of treatments, NCI researcher Curtis Harris told GenomeWeb Daily News.

Harris presented the research at a symposium on miRNAs and human cancer at the American Association for Cancer Research meeting in Denver last week. The work has been submitted for peer review.

While the majority of lung cancer cases are related to smoking, that's not always the case, Harris explained, noting that up to about 15 percent of lung cancer patients are "never-smokers," who have smoked less than 100 cigarettes over their lifetimes.

When Harris and his colleagues looked at genetic similarities and differences between smokers and never-smokers, they found that smokers generally had a higher load of overall DNA damage than never-smokers. That wasn't particularly surprising given the load of carcinogens in cigarette smoke, Harris said.

Even so, while never-smoker tumors usually had fewer mutations, they carried more mutations in EGFR. EGFR mutations were almost exclusively found in these never-smokers, Harris said. "That suggests a different pathway of carcinogenesis in those people," he said.

The team also saw differences in miRNA expression between the two groups. While some miRNAs were expressed in both smoker and never-smoker tumors, the smokers generally had more improperly regulated miRNAs.

But one miRNA stood out: miR-21. Although the researchers found miR-21 dis-regulation in both groups, never-smoker tumors showed higher levels of miR-21 expression.

Past research indicated that miR-21 over-expression could be a consequence of gene amplification or signaling through the signal transducer and activator of transcription 3 or Stat3 pathway, Harris explained.

In this study, Harris and his colleagues found that never-smoker tumors with EGFR mutations also had miR-21 levels that were almost twice as high as those without. That led the team to predict that signaling through the EGFR-pathway also influences miR-21 expression. Indeed, Harris said, lab experiments indicate that inhibiting EGFR leads to decreased miR-21 levels.

Down the road, the team hopes to more fully unravel the relationship between EGFR and miR-21. They're also interested in determining whether inhibiting both EGFR and miR-21 could be an effective strategy for treating cancers that have high miR-21 expression, Harris said.

If so, it would be feasible to measure miR-21 or miRNA levels in the clinic — either using fine needle biopsies to get tumor tissue or assessing tissue from surgically removed tumors — and offer those with high miR-21 levels an anti-miR therapy in conjunction with other cancer therapies.

Still, Harris said he does not want to oversell the potential of such therapy. Although pre-clinical data for various anti-miR therapies has been promising, he said, the anti-miR field is still in its infancy and complications may arise. Even so, he is enthusiastic that the results in the lab stand a good chance of making an impact in the clinic.

"This is a very exciting area in research with a lot of clinical potential," Harris said. "It's moving fast." He expects to see commercialization of miRNA-based therapeutic and prognostic products in the future, "hopefully in a very thoughtful and meticulous way."

In general, anti-miR therapies consist of bits of DNA that are complementary to the miRNAs of interest, though different groups have come up with their own modifications of this plan.

miR-21 is a particularly attractive target, Harris explained, not only because of this research but also in light of previous studies showing that miR-21 is over-expressed in numerous human cancers. For instance, Harris and his colleagues published a paper in the Journal of the American Medical Association last February showing that miR-21 over-expression contributes to colon cancer progression.

Indeed, other groups are already pursuing therapies for miR-21. For instance, a team of researchers, including an investigator from Regulus Therapeutics, reported last year that an antisense oligonucleotide targeting miR-21 effectively prevented and treated heart failure in a mouse model. Based on those results, Regulus is reportedly stepping up efforts to come up with an anti-miR-21 drug for cardiovascular and fibrotic disease.

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