New study helps predict which lung cancer drugs are most likely to work

January 10, 2012, Johns Hopkins Medical Institutions

(Medical Xpress) -- Researchers at Johns Hopkins have shown that DNA changes in a gene that drives the growth of a form of lung cancer can make the cancer’s cells resistant to cancer drugs. The findings show that some classes of drugs won’t work, and certain types of so-called kinase inhibitors like erlotinib—may be the most effective at treating non-small cell lung cancers with those DNA changes. Some kinase inhibitors block a protein known as EGFR from directing cells to multiply.

In their paper published online November 20 in Nature Structural & Molecular Biology, the researchers describe the molecular details of how some work.

“Some anticancer pharmaceuticals that we showed to be ineffective made it to clinical trials because they appeared to prevent the EGFR protein from sending growth signals,” says Philip A. Cole, M.D., Ph.D., Director and E.K. Marshall and Thomas H. Maren Professor of Pharmacology and Molecular Sciences at the Johns Hopkins University School of Medicine. “But we found that different forms of EGFR protein reacted in unexpected ways; and by sorting out these forms in advance, we may be better able to determine which drugs will be better candidates for future clinical trials,” Cole says.”

The researchers found that not all EGFR proteins variations responded to the same drugs that normal EGFR protein did.

The scientists note that non-small cell , the most common form of the disease, generally results from in the EGFR gene, a gene that normally controls cell growth. The genetic changes cause uncontrolled cell growth, the hallmark of cancer.

“Many that used cetuximab and lapatinib were unsuccessful,” says Cole, “and our findings suggest why they failed and why erlotinib succeeded.”

 The new discoveries were prompted by an effort to learn which drugs would work best in non-small cell lung cancer linked to EGFR protein alterations. To start, the researchers first tested cetuximab, a monoclonal antibody that prevents growth factors from binding EGFR. Cetuximab is currently used to treat head and neck and colon cancers, but researchers believed it could be a treatment for lung cancer too.

They added the drug to purified EGFR protein—both normal and two altered versions that have been implicated in lung cancer—and measured the protein’s activity. Normal EGFR had a rate of growth-stimulating activity 100 times less when treated with cetuximab. Both altered EGFRs had much higher rates of growth-stimulating activity, 200 times more than normal EGFR when treated with cetuximab. The researchers concluded that while cetuximab does dampen the activity of normal EGFR protein, it does not significantly reduce the altered EGFR activity, which is not enough to stop cells from growing.

Because cetuximab was unsuccessful at blocking altered EGFR activity, the researchers tested kinase inhibitors. The researchers tested lapatinib, an FDA-approved breast cancer drug, and erlotinib, a drug currently used to treat non-small cell lung and pancreatic cancers. The researchers added different concentrations of lapatinib and erlotinib to the purified normal and altered EGFR proteins and measured the drugs’ effectiveness. Both erlotinib and lapatinib reduced normal EGFR activity, but lapatinib did not block altered EGFR activity. Erlotinib did appear to prevent altered EGFR from working, similar to the way it reduced the normal EGFR protein activity. This led the Hopkins team to conclude that that erlotinib is a better drug treatment for non-small cell lung cancers that are associated with altered forms of EGFR .

Explore further: High EGFR expression a predictor for improved survival with cetuximab plus chemotherapy

Related Stories

High EGFR expression a predictor for improved survival with cetuximab plus chemotherapy

July 5, 2011
High epidermal growth factor receptor (EGFR) expression was a good predictor of which lung cancer patients would survive longer when cetuximab (Erbitux) was added to first-line chemotherapy, according to research presented ...

Recommended for you

How cancer metastasis happens: Researchers reveal a key mechanism

January 18, 2018
Cancer metastasis, the migration of cells from a primary tumor to form distant tumors in the body, can be triggered by a chronic leakage of DNA within tumor cells, according to a team led by Weill Cornell Medicine and Memorial ...

Modular gene enhancer promotes leukemia and regulates effectiveness of chemotherapy

January 18, 2018
Every day, billions of new blood cells are generated in the bone marrow. The gene Myc is known to play an important role in this process, and is also known to play a role in cancer. Scientists from the German Cancer Research ...

These foods may up your odds for colon cancer

January 18, 2018
(HealthDay)—Chowing down on red meat, white bread and sugar-laden drinks might increase your long-term risk of colon cancer, a new study suggests.

The pill lowers ovarian cancer risk, even for smokers

January 18, 2018
(HealthDay)—It's known that use of the birth control pill is tied to lower odds for ovarian cancer, but new research shows the benefit extends to smokers or women who are obese.

Researchers develop swallowable test to detect pre-cancerous Barrett's esophagus

January 17, 2018
Investigators at Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center have developed a simple, swallowable test for early detection of Barrett's esophagus that offers promise ...

Scientists zoom in to watch DNA code being read

January 17, 2018
Scientists have unveiled incredible images of how the DNA code is read and interpreted—revealing new detail about one of the fundamental processes of life.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.