Navigation Links
Genetic variation in East Asians found to explain resistance to cancer drugs

DURHAM, N.C., AND SINGAPORE 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.

Tyrosine kinase inhibitor drugs (TKIs) work effectively in most patients to fight certain blood cell cancers, such as chronic myelogenous leukemia (CML), and non-small-cell lung cancers (NSCLC) with mutations in the EGFR gene.

These precisely targeted drugs shut down molecular pathways that keep these cancers flourishing and include TKIs for treating CML, and the form of NSCLC with EGFR genetic mutations.

Now the team at Duke-NUS Graduate Medical School in Singapore, working with the Genome Institute of Singapore (GIS), Singapore General Hospital and the National Cancer Centre Singapore, has discovered that there is a common variation in the BIM gene in people of East Asian descent that contributes to some patients' failure to benefit from these tyrosine kinase inhibitor drugs.

"Because we could determine in cells how the BIM gene variant caused TKI resistance, we were able to devise a strategy to overcome it," said S. Tiong Ong, M.B.B. Ch., senior author of the study and 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.

"A novel class of drugs called the BH3-mimetics provided the answer," Ong said. "When the BH3 drugs were added to the TKI therapy in experiments conducted on cancer cells with the BIM gene variant, we were able to overcome the resistance conferred by the gene. Our next step will be to bring this to clinical trials with patients."

Said Yijun Ruan, Ph.D., a co-senior author of this study and associate director for Genome Technology and Biology at GIS: "We used a genome-wide sequencing approach to specifically look for structural changes in the DNA of patient samples. This helped in the discovery of the East Asian BIM gene variant. What's more gratifying is that this collaboration validates the use of basic genomic technology to make clinically important discoveries."

The study was published online in Nature Medicine on March 18.

If the drug combination does override TKI resistance in people, this will be good news for those with the BIM gene variant, which occurs in about 15 percent of the typical East Asian population. By contrast, no people of European or African ancestry were found to have this gene variant.

"While it's interesting to learn about this ethnic difference for the mutation, the greater significance of the finding is that the same principle may apply for other populations," said Patrick Casey, Ph.D., senior vice dean for research at Duke-NUS and James B. Duke Professor of Pharmacology and Cancer Biology. "There may well be other, yet to be discovered gene variations that account for drug resistance in different world populations. These findings underscore the importance of learning all we can about cancer pathways, mutations, and treatments that work for different types of individuals. This is how we can personalize cancer treatment and, ultimately, control cancer."

"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."

The researchers found that drug resistance occurred because of impaired production of BH3-containing forms of the BIM protein. They confirmed that restoring BIM gene function with the BH3 drugs worked to overcome TKI resistance in both types of cancer.

"BH3-mimetic drugs are already being studied in clinical trials in combination with chemotherapy, and we are hopeful that BH3 drugs in combination with TKIs can actually overcome this form of TKI resistance in patients with CML and EGFR non-small-cell lung cancer," Ong said. "We are working closely with GIS and the commercialization arm of the Agency for Science, Technology & Research (A*STAR), to develop a clinical test for the BIM gene variant, so that we can take our discovery quickly to the patient."


Contact: Mary Jane Gore
Duke University Medical Center

Related biology news :

1. Rare genetic disorder gives clues to autism, epilepsy, mental retardation
2. Genetic Engineering & Biotechnology News reports on growing role of molecular diagnostics
3. Study finds genetic variant plays role in cleft lip
4. Genetic finding implicates innate immune system in major cause of blindness
5. American College of Medical Genetics receives $13.5M NIH contract
6. Clue to genetic cause of fatal birth defect
7. Can genetic information be controlled by light?
8. The American Society of Human Genetics hosts 58th Annual Meeting in Philadelphia
9. Modern genetics vs. ancient frog-killing fungus
10. Genetic based human diseases are an ancient evolutionary legacy
11. Genetic evidence for avian influenza movement from Asia to North America via wild birds
Post Your Comments:
(Date:11/17/2015)... , November 17, 2015 Paris ...   --> Paris from 17 th ... DERMALOG, the biometrics innovation leader, has invented the first combined ... on the same scanning surface. Until now two different scanners ... one scanner can capture both on the same surface. ...
(Date:11/16/2015)... SAN JOSE, Calif. , Nov 16, 2015 ... leading developer of human interface solutions, today announced ... new Synaptics TouchView ™ touch controller and ... the architectural revolution of smartphones. These new TDDI ... and include TD4100 (HD resolution), TD4302 (WQHD resolution), ...
(Date:11/11/2015)... 2015   MedNet Solutions , an innovative SaaS-based eClinical ... is pleased to announce that it will be a Sponsor ... event, to be held November 17-19 in Hamburg ... demonstrations of iMedNet , MedNet,s easy-to-use, proven ... has been able to deliver time and cost savings ...
Breaking Biology News(10 mins):
(Date:11/24/2015)... TEL AVIV, Israel , Nov. 24, 2015  Tikcro Technologies Ltd. ... be held on December 29, 2015 at 11:00 a.m. Israel ... & Co., Electra Tower, 98 Yigal Allon Street, 36 th Floor, ... , election of Eric Paneth and Izhak Tamir ... and Rami Skaliter as external directors; , approval of an ...
(Date:11/24/2015)... ... November 24, 2015 , ... In ... paramount. Insertion points for in-line sensors can represent a weak spot where leaking ... 781/784 series of retractable sensor housings , which are designed to tolerate extreme ...
(Date:11/24/2015)... , Nov. 24, 2015 /CNW Telbec/ - ProMetic Life Sciences ... today that Mr. Pierre Laurin , President and Chief ... at the upcoming Piper Jaffray 27 th Annual Healthcare ... on December 1-2, 2015. st , at ... one-on-one meetings throughout the day. The presentation will be available ...
(Date:11/24/2015)... INCLINE VILLAGE, Nev. , Nov. 24, 2015  PDL ... John P. McLaughlin , the company,s president and chief ... Piper Jaffray Healthcare Conference next week in New ... and will occur on Tuesday, December 1, 2015 at 9:30 ... and Presentations." Please connect to the website at least 15 ...
Breaking Biology Technology: