Genetic variation in East Asians found to explain resistance to tyrosine kinase inhibitor drugs
No people of European or African ancestry were found to have variation in the BIM gene
A multinational research team has identified the reason why some patients fail to respond to some of the most successful cancer drugs. Tyrosine kinase inhibitors (TKIs) work effectively in most patients with chronic myelogenous leukaemia (CML) and non-small-cell lung cancers (NSCLC) with mutations in the EGFR gene. Now the team at Duke-NUS Graduate Medical School in Singapore, working with the Genome Institute of Singapore, 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.
According to S. Tiong Ong, MBB 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 Centre, the study team could determine in cells how the BIM gene variant caused TKI resistance, and therefore was able to devise a strategy to overcome it.
Genome-wide sequencing approach
When a novel class of BH3 drugs were added to the TKI therapy in experiments conducted on cancer cells with the BIM gene variant, researchers were able to overcome the resistance conferred by the gene. Their next step will be to bring this to clinical trials with patients.
They 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.
f the drug combination does override TKI resistance, this will be good news for those with the BIM gene variant, which occurs in about 15% of the typical East Asian population. By contrast, no people of European or African ancestry were found to have this gene variant.
According to Patrick Casey, PhD, senior vice dean for research at Duke-NUS and James B Duke Professor of Pharmacology and Cancer Biology, it's interesting to learn about this ethnic difference for the mutation, and the greater significance of the finding is that the same principle may apply for other populations. There may well be other, yet to be discovered gene variations that account for drug resistance in different world populations.
Impaired production of BH3-containing forms of the BIM protein
The study team estimated that about 14,000 newly diagnosed East Asian CML and EGFR non-small-cell lung cancer patients per year will carry the gene variant. Notably, EGFR NSCLC is much more common in East Asia, and accounts for about 50% of all NSCLC in East Asia, compared to only 10% 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 researchers are hopeful that BH3 drugs in combination with TKIs can actually overcome this form of TKI resistance. The study team is working closely with Genome Institute of Singapore and the commercialization arm of the Agency for Science, Technology & Research (A*STAR), to develop a clinical test for the BIM gene variant.
The study was supported by grants from the National Medical Research Council (NMRC) of Singapore; Biomedical Research Council of A*STAR, Singapore; Genome Institute of Singapore; Singapore General Hospital; and two NMRC Clinician Scientist Awards.
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