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

Scientists at Duke-NUS Medical School and their collaborators have identified a common inherited genetic variation among East Asians that contributes to drug resistance and drives the aggressive growth of cancer cells in patients with chronic myeloid leukemia.

To address this problem, the team’s groundbreaking approach is to inhibit the action of a protein called MCL-1. Laboratory studies have shown promising results in effectively killing cancer cells that are resistant to conventional treatments.

These results were published in the journal leukemiademonstrate the importance of genetic profiling in developing more precise and effective treatments for cancer patients.

One-sixth of all human cancers have genetic variations, but few studies have demonstrated how this affects treatment outcomes. The team tried to answer this question by focusing on an inherited genetic variation that affects patients with leukemia.

In 2020, leukemia (blood cancer) accounted for approximately 2.5% of all new cancer cases and 3.1% of all deaths worldwide. 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 the Singapore General Hospital and the Jackson Laboratory, developed the first preclinical model with a common genetic variation in the population of the East Asian region, which includes Chinese, Japanese and Koreans.

About 12 to 15% of people in this region carry an inherited genetic variation in a protein called BCL-2 interacting death mediator (BIM), which is critical 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 developed preclinical model and showed that the variation leads to the production of alternative versions of the BIM protein, which in turn helps cancer cells escape cell death. This allows the tumor cells to survive longer and multiply more aggressively, which contributes 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 commonly used. However, patients with the BIM variant often do not respond well to imatinib because the treatment kills fewer cancer cells.

Dr. Giselle Nah, a research fellow in the Duke-NUS Program in Cancer and Stem Cell Biology and lead author of the study, said: “We found that leukemia cells with the BIM variant had higher survival rates than those without it.” These cells were resistant to the BIM variant Cell death that imatinib normally triggers. This resistance allowed the leukemia to progress more aggressively.

To delve deeper into the mechanisms, the team used advanced profiling techniques to examine how different cancer cells rely on different proteins for survival.

The joint first author Dr. Yu Mengge, a research fellow in the Duke-NUS Cancer and Stem Cell Biology Program, explained: “We found that leukemia cells with the BIM variant rely 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 addressed with new and more effective treatments.”

Professor Ong Sin Tiong, a clinical scientist in the Duke-NUS Cancer and Stem Cell Biology Program and senior author of the study, added: “Based on what we learned, we tried a new treatment called an MCL-1 -Blocker combined with imatinib The results were encouraging as the combination was much more effective at killing the resistant leukemia cells than using imatinib alone.

“This suggests that targeting MCL-1 could help combat the resistance that occurs in patients with chronic myelogenous leukemia with the BIM variant to reduce the likelihood of disease progression.”

This discovery could be groundbreaking for patients with this variant.

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

He said: “Getting the right 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 results 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 significant implications for other types of cancer, such as certain types of lung cancer, where treatment occurs by triggering the BIM protein to kill tumor cells. Scientists hope to conduct further research in this area to allow more patients to benefit from the benefits of precision medicine.