AsianScientist (Mar. 21, 2012) – Researchers from Singapore and Japan have discovered that a gene variant commonly found in individuals of East Asian descent may be responsible for resistance to some targeted cancer drugs used to treat certain types of leukemia and lung cancer.
Patients with chronic myelogenous leukemia (CML) are currently treated with tyrosine kinase inhibitors (TKIs) such as Gleevec. Although these drugs are effective in most patients with CML, a significant number of CML patients do not respond well to TKI treatment.
To understand why, the researchers looked for genetic differences between patients who responded well to TKI treatment and those that did not.
In their study, published online in Nature Medicine, the researchers discovered that many TKI-resistant CML patients had a particular variant of the BIM gene which is characterized by a region of missing DNA within the gene, known as a deletion polymorphism.
This deletion polymorphism was found to be common in East Asians (about 12 percent of healthy Chinese and Japanese individuals have it) but not detected in people of African and European descent.
East Asian CML patients who have this BIM deletion polymorphism are three times more likely to respond poorly to Gleevec treatment, compared with patients who do not have the gene variant.
It is also estimated that about 20 percent of East Asian CML patients who are resistant to Gleevec may have this BIM deletion polymorphism.
Therefore, this East Asian variant of the BIM may be part of the reason why East Asian CML patients have poorer response rates when treated with Gleevec, compared with patients in Europe and North America.
The study also found that this same deletion polymorphism may be responsible for drug resistance in EGFR-mutated non-small-cell lung cancer (EGFR NSCLC) which is also commonly treated with TKIs.
“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,” said Dr. S. Tiong Ong, the senior author of the study.
“Because we could determine in cells how the BIM gene variant caused TKI resistance, we were able to devise a strategy to overcome it.”
The strategy Dr. Ong was referring to is novel class of drugs called BH3-mimetics. When BH3 drugs were added to the TKI therapy in experiments conducted on cancer cells with the BIM gene variant, the researchers were able to overcome the resistance conferred by the gene.
The team’s next step will be to bring their BH3-based treatment to clinical trials with patients.
Source: Duke-NUS Graduate Medical School Singapore.
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