New discovery could help improve treatment of drug-resistant leukemia

Researchers at Duke-NUS School of Medicine have identified an inherited genetic variation that contributes to drug resistance by promoting aggressive cancer cell growth in patients with chronic myeloid leukemia.

One in six human cancers have the genetic variation, but very few studies have identified how it affects treatment outcomes.

 

In 2020, leukemia (a cancer of the blood) accounted for about 2.5 percent of all new cases of malignant neoplasms and 3.1 percent of deaths worldwide. One subtype of the disease is chronic myeloid leukemia (CML), which primarily affects the bone marrow that produces blood cells.

 

Duke-NUS scientists, in collaboration with their partners, have developed the first preclinical model with a genetic variation common in the population of the East Asian region, which includes Chinese, Japanese and Koreans. About 12 to 15 percent of people from this region have an inherited genetic variation in a protein called BCL-2, which interacts with the protein mediator of death (BIM), which is critical for regulating the killing of damaged or unwanted cells.

The researchers conducted a series of experiments showing that the presence of variation leads to the production of alternative versions of the BIM protein, which in turn helps cancer cells evade destruction. As a consequence, tumor cells survive longer and are able to multiply more aggressively, contributing to disease progression.

One of the most common treatments for chronic myeloid leukemia is a class of drugs known as tyrosine kinase inhibitors, of which imatinib is the most widely used. However, patients with a variation of BIM often respond poorly to imatinib: they have fewer cancer cells destroyed as a result of treatment.

To further understand the mechanisms of this process, the team used advanced gene profiling techniques to study how different tumor cells depend on different proteins for survival.

The study’s first author Dr. Yu Mengge, a researcher in the Duke-NUS Cancer Biology and Stem Cell Program, said: “We found that leukemia cells with BIM variation are highly dependent on a protein called MCL-1 for survival. This important discovery has highlighted a potential vulnerability in these imatinib-resistant malignant cells that could be targeted with new and more effective therapies.”

Based on this knowledge, the researchers tried a new treatment that used a combination of an MCL-1 blocker with imatinib: the results were encouraging, as the combination was much more effective at killing resistant leukemia cells than imatinib alone. This suggests that targeting MCL-1 may help manage the resistance seen in chronic myeloid leukemia patients with BIM variation and reduce the likelihood of disease progression.

For patients with this variation, this discovery could be a game changer.

Getting the right oncology treatment as early as possible is critical to improve patient outcomes and quality of life. Given the prevalence of the BIM variation in the East Asian population, it is crucial to understand its impact on cancer treatment. The results of this study suggest that genetic testing for this variant at diagnosis may improve treatment outcomes.

The findings could also have significant implications for other cancers, such as certain types of lung cancer, where the BIM protein destroys tumor cells during treatment. Scientists hope to conduct further research in this area to bring the benefits of precision medicine to more patients.