Scientists explored how a specific inherited genetic variation found frequently among East Asians affects drug resistance in cancer cells, leading to more aggressive cancer development. The research team tested a targeted therapy for this genetic group by inhibiting the function of a protein known as MCL-1, which showed success in eliminating many cancer cells in laboratory experiments.
Researchers at Duke-NUS Medical School, along with their collaborators, have discovered a genetic variation that is commonly inherited among East Asians and plays a role in drug resistance, encouraging the rapid growth of cancer cells in patients suffering from chronic myeloid leukemia. To tackle this issue, the team’s innovative approach focuses on blocking the action of a protein called MCL-1. Laboratory tests have shown encouraging results in effectively destroying cancer cells that are resistant to standard therapies. These results, shared in the journal Leukemia, emphasize the significance of genetic profiling to create tailored and more effective cancer treatments.
About one in six cancers contains genetic variations, but few studies have clarified their impact on treatment results. The team aimed to uncover this by investigating a genetic variation that particularly affects leukemia patients.
In 2020, leukemia (a blood cancer) made up an estimated 2.5% of new cancer cases and accounted for 3.1% of cancer-related deaths worldwide. Chronic myeloid leukemia (CML) is a form of leukemia that mainly targets the bone marrow, where blood cells are produced.
The scientists from Duke-NUS, in collaboration with partners like Singapore General Hospital and The Jackson Laboratory, created the first pre-clinical model featuring a widely prevalent genetic variation among East Asians, including Chinese, Japanese, and Korean populations. Approximately 12 to 15 percent of individuals in this area carry a genetic variation in a protein known as BCL-2 interacting death mediator (BIM). This protein is crucial for controlling cell death to eliminate damaged or unwanted cells, a process that many cancer therapies utilize to kill tumor cells.
Through a series of controlled experiments utilizing their specialized pre-clinical model, the researchers found that this variation leads to the creation of different versions of the BIM protein, allowing cancer cells to resist cell death. As a result, these tumor cells survive longer and proliferate more vigorously, promoting disease advancement.
One of the primary treatments for chronic myeloid leukemia involves drugs known as tyrosine kinase inhibitors, with imatinib being one of the most commonly used. However, patients who have the BIM genetic variation frequently do not respond effectively to imatinib, resulting in fewer cancer cells being eradicated by the treatment.
Dr. Giselle Nah, a research fellow from Duke-NUS’ Cancer and Stem Cell Biology Programme and the study’s lead author, commented:
“Our study revealed that leukaemia cells with the BIM variation exhibited higher survival rates compared to those without it. Specifically, these cells resisted the cell death that imatinib typically induces, allowing the leukemia to develop more aggressively.”
To further investigate the underlying mechanisms, the research team employed advanced profiling techniques to analyze how various cancer cells depend on different proteins for their survival.
Joint first author Dr. Yu Mengge, also a research fellow at Duke-NUS’ Cancer and Stem Cell Biology Programme, stated:
“We discovered that leukaemia cells possessing the BIM variation were significantly reliant on a protein called MCL-1 for their survival. This crucial finding unveiled a potential weakness in these imatinib-resistant cancer cells that could be targeted with new, more effective therapies.”
Professor Ong Sin Tiong, a clinician-scientist from Duke-NUS’ Cancer and Stem Cell Biology Programme and senior author of the study, remarked:
“From our findings, we tested a new treatment that combined an MCL-1 blocker with imatinib. The results were quite promising, as this combination proved to be significantly more effective at eliminating resistant leukemia cells than using imatinib alone. This suggests that targeting MCL-1 could be beneficial in overcoming the resistance observed in chronic myeloid leukaemia patients with the BIM variation, potentially reducing the risk of disease progression.”
This discovery could represent a major breakthrough for patients with this genetic variation.
Duke-NUS Associate Professor Charles Chuah, a Senior Consultant at the Department of Haematology, Singapore General Hospital, and National Cancer Centre Singapore, collaborated on this study. He emphasized:
“Receiving the appropriate cancer treatment as soon as possible is critical for improving patient outcomes and quality of life. Considering the widespread occurrence of the BIM variation in the East Asian population, it is vital to comprehend its effects on cancer therapies. Our study suggests that genetic testing for this variant at the time of diagnosis could enhance outcomes by identifying patients who might benefit from more aggressive treatments.”
These insights could significantly influence treatment for other cancers, including certain lung cancer types, where therapies are designed to prompt the BIM protein to kill tumor cells. The researchers aspire to continue their investigations in this field to extend the advantages of precision medicine to a broader patient demographic.
Duke-NUS stands out as a leader in medical education and biomedical research, merging fundamental scientific inquiry with applied knowledge to enhance understanding of prevalent diseases and develop innovative treatment strategies to improve lives in Singapore and beyond.
