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

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

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 ...

Recommended for you

Multifaceted genetic impact of training

September 23, 2016

Endurance training changes the activity of thousands of genes and give rise to a multitude of altered DNA-copies, RNA, researchers from Karolinska Institutet report. The study, which also nuances the concept of muscle memory, ...

Controlling cell-fate decisions

September 23, 2016

Rafal Ciosk and his group at the FMI have identified an important link between the Notch signaling pathway and PRC2-mediated gene silencing. They showed that a fine balance between epigenetic silencing and signaling is crucial ...

Unravelling the genetic mystery behind mitochondrial disease

September 15, 2016

Researchers from the Monash Biomedicine Discovery Institute in Melbourne have identified two new genes linked to a major cause of mitochondrial disease. Their research opens the way for better genetic diagnosis of the disease ...

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.