Inhibiting specific protein action could lead to precision therapy for some patients with drug-resistant leukemia microbiologystudy

Scientists from Duke-NUS Medical School and their 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, with laboratory studies showing promising results in effectively killing cancer cells resistant to conventional treatments.

These findings, which were published in the journal Leukemia, demonstrate the importance of genetic profiling to develop precise and more effective treatments for patients with cancer.

One-sixth of human cancers harbor genetic variations, but few studies have established how that affects treatment outcomes. The team sought to answer this question by homing in on an inherited genetic variation that affects patients with leukemia.

In 2020, leukemia (cancer of the blood) accounted for approximately 2.5% of all new cancer cases and 3.1% of deaths globally. Of these, chronic myeloid leukemia (CML) is a subtype that primarily affects the bone marrow, which produces blood cells.

The Duke-NUS scientists, in collaboration with their partners, including Singapore General Hospital and The Jackson Laboratory, developed the first pre-clinical model with a common genetic variation among the population of the East Asian region, which includes Chinese, Japanese and Korean people.

About 12 to 15% of people from this region carry an inherited genetic variation in a protein called BCL-2 interacting death mediator (BIM), which is crucial for regulating cell death to eliminate damaged or unwanted cells. Many cancer treatments trigger this process to destroy tumor cells.

The researchers then conducted a series of experiments using their specially designed pre-clinical 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, the 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, with imatinib being one of the most widely used. However, patients with the BIM variation often don’t respond well to imatinib, with fewer cancer cells being killed by the treatment.

Dr. Giselle Nah, a research fellow from Duke-NUS’s Cancer and Stem Cell Biology Program and a first author of the study, said, “We discovered that leukemia cells with the BIM variation had higher survival rates compared to those without it. Specifically, these cells were resistant to the cell death that imatinib would typically induce. This resistance allowed the leukemia to progress more aggressively.”

To dig deeper into the mechanisms at play, the team used advanced profiling techniques to study how different cancer cells depend on various proteins for survival.

Joint first author Dr. Yu Mengge, a research fellow from Duke-NUS’s Cancer and Stem Cell Biology Program, explained, “We found that leukemia cells with the BIM variation relied heavily 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 targeted with new and more effective treatments.”

Professor Ong Sin Tiong, a clinician-scientist from Duke-NUS’s Cancer and Stem Cell Biology Program and the study’s senior author, added, “Based on what we learned, we tried a new treatment that combined an MCL-1 blocker with imatinib. The results were encouraging, as the combination was much more efficient at killing the resistant leukemia cells than using imatinib alone.

“This indicates that targeting MCL-1 could help tackle the resistance found in chronic myeloid leukemia patients with the BIM variation, to reduce the chances of disease progression.”

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

Duke-NUS Associate Professor Charles Chuah, a Senior Consultant at the Department of Hematology, Singapore General Hospital and National Cancer Center Singapore, collaborated on the study.

He said, “Getting the right cancer treatment as early as possible is crucial in improving patient outcome 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. Our findings suggest that genetic testing for this variant at diagnosis can improve outcomes by identifying patients who may benefit from more aggressive treatments.”

These findings could have significant implications for other cancers, such as certain types of lung cancer, where treatment is administered by triggering the BIM protein to kill tumor cells. The scientists hope to conduct further research in this area to deliver the benefits of precision medicine to more patients.