Gene to Blame for Drug Resistance

TKIs fail to work in some East Asians because of variation in BIM gene

(RxWiki News) Targeted drugs work by attacking and shutting down the molecular activities that keep cancers thriving and growing. These drugs have saved the lives of thousands of people with cancer. But they don't work in some people.

An international research effort has discovered that people of East Asian descent don't always respond to a class of cancer medications known as tyrosine kinase inhibitors (TKIs) because of a genetic variation. Scientists may have found a way to overcome this resistance.

"Ask your doctor how you will know if a drug is not working."

Scientists at the Duke-NUS Graduate Medical School in Singapore led the research team that included investigators from the Genome Institute of Singapore (GIS), Singapore General Hospital and the National Cancer Centre Singapore.

TKIs have changed the course of treatment of some blood cancers including chronic myeloid leukemia (CML) and non-small-cell lung cancers (NSCLC) that have mutations in the epidermal growth factor receptor (EGFR) gene.

In this study, the team discovered that common alteration in the BIM gene in East Asian people contributes to the failure of TKIs.

Senior study author, Dr. S. Tiong Ong, explains that by understanding how the genetic variant caused the resistance, the team was able to find a way around it - at least in the lab.

Ong, who is associate professor in the Cancer and Stem Cell Biology Signature Research Programme at Duke-NUS and Division of Medical Oncology, Department of Medicine, at Duke University Medical Center, says that a novel class of drugs called BH3-mimetics offered solutions.

When these drugs were added to TKIs used on cancer cells with the genetic mutation, the resistance was overcome.

The next step will be to conduct clinical trials to see if this works with patients, Ong said.

If this combination approach works in humans, it will be good news for the roughly 15 percent of the typical East Asian population who have the BIM gene mutation, which was not found in people of European or African ancestry.

"We estimate that about 14,000 newly diagnosed East Asian CML and EGFR non-small-cell lung cancer patients per year will carry the gene variant," Ong said. "Notably, EGFR NSCLC is much more common in East Asia, and accounts for about 50 percent of all non-small-cell lung cancers in East Asia, compared to only 10 percent in the West."

This study was published online in Nature Medicine on March 18, 2012.

The research was supported by grants from the National Medical Research Council (NMRC) of Singapore; Biomedical Research Council (BMRC) of A*STAR, Singapore; Genome Institute of Singapore; Singapore General Hospital; and two NMRC Clinician Scientist Awards.

No conflicts of interest were disclosed.

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Review Date: 
March 19, 2012