Rethinking Healthcare

Genetic mutations: why lung cancer drugs fail

Posting in Cancer

Tumors have many tricks when dodging drugs, including genetic changes. By uncovering various escape routes, two new studies offer hopes for therapies tailored to cut them off.

Even with drugs that are genetically targeted to attack them, tumors have many ways to dodge, evade, and survive. By uncovering these escape routes, two new studies offer hope for therapies tailored to cut them off. Nature News reports.

Some lung cancers have genetic mutations that activate a protein called epidermal growth factor receptor (EGFR). The improper activation of this protein leads to uncontrolled cell division – a hallmark of cancer.

There are 2 drugs that prevent tumor growth by blocking EGFR in tumors. These ‘EGFR inhibitors’ are known as gefitinib (AstraZeneca's Iressa) and erlotinib (Genentech's Tarceva).

They help most patients, but no one knows why the rest respond poorly, if at all.

1. Perhaps other genes modify a patient's response to drugs.

To test this, Charles Sawyers from Memorial Sloan-Kettering Cancer Center and his colleagues reduced the activity of cancer-related genes, and then tested the cells to see if this made them more sensitive to drugs.

Of more than 2,000 genes screened, 36 affected sensitivity to EGFR inhibitors. Half of those are linked to a single protein called NF-κB, which governs stress responses.

NF-κB blockers, used in combination with EGFR inhibitors, could fight stubborn tumors. In a trial of 52 lung cancer patients, those with high levels of a protein that blocks NF-κB responded better to erlotinib than those with low levels.

The team is now testing the combination therapy in animals. This study was published in Nature this past week.

2. Another problem with cancer therapies is that, even if patients respond well at first, the drugs eventually fail. The effects of EGFR inhibitors typically last a year before the tumors, now drug-resistant, return.

To characterize some ways that a tumor shields itself from drugs, Jeffrey Engelman from the Massachusetts General Hospital and his team examined resistant tumors in 37 patients.

They saw EGFR-related mutations that allow the protein to dodge inhibitors, as expected. But they also observed tumors behaving unexpectedly – by amplifying the gene for EGFR or picking up mutations in another cancer-promoting gene.

This study was published in Science Translational Medicine this past week.

Finding so many paths to drug resistance means that patients will need an arsenal of possible drug combinations to conquer the disease. "It is humbling to see the many resistance mechanisms that can occur," says Engelman. "It underscores the challenges ahead."

Via Nature News.

Image: tumor in the left lung via Wiki

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Janet Fang

Contributing Editor

Janet Fang has written for Nature, Discover and the Point Reyes Light. She is currently a lab technician at Lamont-Doherty Earth Observatory. She holds degrees from the University of California, Berkeley and Columbia University. She is based in New York. Follow her on Twitter. Disclosure