Wayward gene found, vanquished in some East Asians with CML and NSCLC

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Researchers have not only found that some cancer patients of East Asian descent fail to benefit from tyrosine kinase inhibitors (TKIs) due to a common variation in the BIM gene, but they have also learned how to overcome this resistance.

TKIs elicit high response rates among persons with kinase-driven malignancies including chronic myeloid leukemia (CML) and non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) genetic mutations. However, the extent and duration of these responses appeared to vary based on genetic modifiers.

A team led by S. Tiong Ong, MBBCh, of Duke–National University of Singapore (NUS) in Singapore and the medical oncology division at Duke University Medical Center in Durham, North Carolina, used DNA sequencing to pursue this hypothesis. The investigators' work revealed that patients with CML or EGFR NSCLC who harbored the BIM mutation did, in fact, have a significantly inferior response to TKIs than did persons without the variant.

The BIM mutation occurs in approximately 15% of the typical East Asian population, but Ong and colleagues did not find it in anyone of European or African ancestry. They estimated that each year, 14,000 East Asian patients newly diagnosed with CML or EGFR NSCLC would carry the BIM mutation. As Ong pointed out in a statement describing the group's findings, which were reported in Nature Medicine, EGFR NSCLC is much more common in East Asia than in the West: In East Asia, it accounts for about 50% of all cases of NSCLC, compared with only approximately 10% in the West.

To combat the resistance to TKIs conferred by the BIM mutation, the researchers added a novel class of drugs called BH3-mimetics to the TKI therapy in experiments conducted on cancer cells. The BH3-mimetic agents helped restore BIM gene function and overcome TKI resistance in both CML and EGFR NSCLC.

“Because we could determine in cells how the BIM gene variant caused TKI resistance, we were able to devise a strategy to overcome it,” noted Ong. “Our next step will be to bring this to clinical trials with patients.”

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