A genetic variation common in East Asian populations has been linked to cancer drug resistance

August 2, 2012

Tyrosine kinase inhibitors (TKIs) kill cancerous cells by inducing programmed cell death. They are of enormous therapeutic benefit to patients with chronic myeloid leukemia (CML) and certain types of lung cancer, but their effectiveness may vary from individual to individual. Previous studies have estimated that one in five patients finds TKIs to be ineffective. An international team of researchers including Yijun Ruan and Axel Hillmer at the A*STAR Genome Institute of Singapore, Sin Tiong Ong and King Pan Ng at the Duke-National University of Singapore Graduate Medical School, Charles Chuah at the Department of Haematology, Singapore General Hospital and Darren Wan-Teck Lim at the National Cancer Centre has now identified a common genetic variation linked with resistance to TKIs.

Ng, Hillmer and their colleagues sequenced and compared the genomes of five CML patients, three of whom were resistant to treatment with TKIs, focusing on several that are known to be involved in the cell death signaling pathway. The researchers found that what the three TKI-resistant patients all had in common was a 2,903 base pair deletion in the non-coding region of the BIM gene, which encodes a member of the BCL2 family of cell death genes.

They then screened the genomes of more than 2,500 healthy individuals, and found that this deletion is a common variation that occurs in approximately one eighth of East Asian individuals but is not found in Africans or Europeans. Further experiments revealed that the deletion alters processing of the that is transcribed from the BIM gene. As a result of this, the coding sequence of the cell death activation domain is preferentially removed, so that the BIM proteins synthesized from the transcript are faulty.

Finally, the researchers showed that the deletion in the BIM gene is a useful biomarker that predicts which patients are at risk for developing TKI resistance. They examined the responses of 203 East Asian cancer patients to the drug imatinib, and found that CML patients with the deletion were more likely to be resistant to it.

In lung cancer patients, the deletion was associated with the duration of the drug response, and predicted a shorter period of survival without disease progression. Those with the deletion had progression-free periods of about six-and-a-half months, on average, compared to an average of nearly 12 months in those without it.

“Asian CML patients could be screened for the presence of the deletion to determine the ones who have a higher chance of being resistant to TKI treatment,” says Hillmer. “It will be interesting to investigate the frequency of the deletion polymorphism in other populations and to translate the findings in the clinical practice.”

Explore further: BIM gene variation in East Asians found to explain resistance to cancer drugs

More information: Ng, K. P. et al. A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer. Nature Medicine 18, 521–528 (2012). dx.doi.org/10.1038/nm.2713

Related Stories

BIM gene variation in East Asians found to explain resistance to cancer drugs

March 18, 2012
A multi-national research team led by scientists at Duke-NUS Graduate Medical School has identified the reason why some patients fail to respond to some of the most successful cancer drugs.

New drug shows potential for treatment-resistant leukemia

April 11, 2011
A study from Tufts Medical Center researchers published today finds that a novel drug shows promise for treating leukemia patients who have few other options because their disease has developed resistance to standard treatment.

Targeted drug helps leukemia patients who do not benefit from initial therapy

February 27, 2012
A new study has found that patients with chronic myeloid leukemia (CML) who have not responded to interferon treatments experience long-term benefits when they switch to the targeted drug imatinib. Published early online ...

Double whammy: RNAi enhances lung cancer therapy

March 20, 2012
Non-small cell lung cancer (NSCLC), the most common form of lung cancer, is usually treated with surgery and chemotherapy. However, a small group of patients can also be helped by treatment with tyrosine kinase inhibitors ...

Asian lung cancer patient survival exceeds Caucasians' on multiple regimens

June 1, 2011
Asian non-small cell lung cancer (NSCLC) patients survive longer than Caucasians no matter how many drugs are given in a first-line setting, and the effect was apparent both before and after the introduction of targeted therapies ...

Recommended for you

New approach to studying chromosomes' centers may reveal link to Down syndrome and more

November 20, 2017
Some scientists call it the "final frontier" of our DNA—even though it lies at the center of every X-shaped chromosome in nearly every one of our cells.

Genome editing enhances T-cells for cancer immunotherapy

November 20, 2017
Researchers at Cardiff University have found a way to boost the cancer-destroying ability of the immune system's T-cells, offering new hope in the fight against a wide range of cancers.

A math concept from the engineering world points to a way of making massive transcriptome studies more efficient

November 17, 2017
To most people, data compression refers to shrinking existing data—say from a song or picture's raw digital recording—by removing some data, but not so much as to render it unrecognizable (think MP3 or JPEG files). Now, ...

Genetic mutation in extended Amish family in Indiana protects against aging and increases longevity (Update)

November 15, 2017
The first genetic mutation that appears to protect against multiple aspects of biological aging in humans has been discovered in an extended family of Old Order Amish living in the vicinity of Berne, Indiana, report Northwestern ...

US scientists try first gene editing in the body

November 15, 2017
Scientists for the first time have tried editing a gene inside the body in a bold attempt to permanently change a person's DNA to try to cure a disease.

Genetic variant prompts cells to store fat, fueling obesity

November 13, 2017
Obesity is often attributed to a simple equation: People are eating too much and exercising too little. But evidence is growing that at least some of the weight gain that plagues modern humans is predetermined. New research ...

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.