Duke-NUS Medical School scientists and collaborators have identified an inherited genetic variation prevalent among East Asians that contributes to drug resistance, driving the aggressive growth of cancer cells in patients with chronic myeloid leukemia. To address this, the team’s pioneering approach involves inhibiting the action of a protein called MCL-1, and laboratory studies show promising results in effectively eliminating cancer cells resistant to conventional treatments. These findings, which were published in the journal Leukemiademonstrate the importance of genetic profiling to develop precise and more effective treatments for cancer patients.
One-sixth of human cancers harbor genetic variations, but few studies have established how that affects treatment outcomes. The team attempted to answer this question by focusing on an inherited genetic variation that affects leukemia patients.
In 2020, leukemia (blood cancer) accounted for approximately 2.5 percent of all new cancer cases and 3.1 percent of deaths globally. Of these, chronic myeloid leukemia (CML) is a subtype that primarily affects the bone marrow, which produces blood cells.
Duke-NUS scientists, in collaboration with partners including Singapore General Hospital and Jackson Laboratory, developed the first preclinical model with a common genetic variation among the population of the East Asian region, which includes Chinese, Japanese and Koreans. . About 12 to 15 percent of people in this region carry an inherited genetic variation in a protein called BCL-2-interacting death mediator (BIM), which is crucial for regulating cell death and eliminating damaged or damaged cells. unwanted. Many cancer treatments trigger this process to destroy tumor cells.
The researchers then performed a series of experiments using their specially designed preclinical model, showing that the variation results in the production of alternative versions of the BIM protein, which, in turn, helps cancer cells evade cell death. Consequently, tumor cells survive longer and can multiply more aggressively, contributing to disease progression.
One of the most common treatments for chronic myeloid leukemia is a class of medications known as tyrosine kinase inhibitors, with imatinib being one of the most commonly used. However, patients with the BIM variation often do not respond well to imatinib, and the treatment kills fewer cancer cells.
Dr Giselle Nah, researcher at the Duke-NUS Cancer and Stem Cell Biology Program and first author of the study, said:
“We found that leukemic cells with the BIM variation had higher survival rates compared to those without it. Specifically, these cells were resistant to the cell death that would normally be induced by imatinib. This resistance allowed the leukemia to progress more aggressive.”
To delve deeper into the mechanisms at play, the team used advanced profiling techniques to study how different cancer cells depend on various proteins to survive.
Joint first author Dr Yu Mengge, a researcher at the Duke-NUS Cancer and Stem Cell Biology Programme, said:
“We found that leukemic cells with the BIM variation were highly dependent on a protein called MCL-1 to stay alive. This important discovery revealed a potential vulnerability in these imatinib-resistant cancer cells that could be addressed with new, more effective treatments.” .
Professor Ong Sin Tiong, clinical scientist at the Duke-NUS Cancer and Stem Cell Biology Program and senior author of the study, said:
“Based on what we learned, we tested a new treatment that combined an MCL-1 blocker with imatinib. The results were encouraging, as the combination was much more effective in killing resistant leukemia cells than using imatinib alone. This indicates that targeting to MCL -1 could help address the resistance found in CML patients with the BIM variation, to reduce the chances of disease progression.”
For patients with this variation, this discovery could be a game-changer.
Collaborating on the study was Duke-NUS Associate Professor Charles Chuah, senior consultant at the Department of Hematology at Singapore General Hospital and the Singapore National Cancer Centre. He said:
“Receiving appropriate cancer treatment as early as possible is crucial to improving patient outcomes and quality of life. Given the prevalence of BIM variation in the East Asian population, it is crucial to understand its impact on cancer treatment.” “Our findings suggest that genetic testing for this variant at diagnosis may improve outcomes by identifying patients who may benefit from more aggressive treatments.”
These findings could have important implications for other cancers, such as certain types of lung cancer, where treatment is delivered by activating the BIM protein to kill tumor cells. Scientists hope to conduct more research in this area to bring the benefits of precision medicine to more patients.
Duke-NUS is a global leader in medical education and a biomedical research powerhouse, combining basic scientific research with translational knowledge to provide a better understanding of common diseases and develop new treatment approaches to improve the lives of people in Singapore and beyond.