In a major scientific breakthrough, researchers from McMaster University, Cleveland Clinic, and the Case Comprehensive Cancer Center have uncovered how a protein commonly linked to Alzheimer’s disease also plays a critical role in the spread of lung cancer to the brain. The discovery could pave the way for repurposing existing Alzheimer’s drugs to halt or slow brain metastases in cancer patients.
Published on July 2, 2025, in Science Translational Medicine, the study identifies the protein BACE1 as a key driver in the development of brain metastases—tumors that migrate to the brain from other parts of the body in patients with non-small cell lung cancer. These metastases are particularly devastating, affecting up to 40% of such patients, and are notoriously difficult to treat.
“We’ve always associated BACE1 with Alzheimer’s disease, so to find it playing a major role in lung cancer brain metastases is an important discovery,” said Dr. Sheila Singh, senior author of the study and director of McMaster’s Centre for Discovery in Cancer Research. “It’s a reminder that cancer can hijack biological pathways in ways we don’t yet fully understand.”
To reach this conclusion, the team employed a cutting-edge genome-wide in vivo CRISPR activation screen. This technique allowed researchers to systematically turn on thousands of genes in lung cancer cells, which were then implanted into mice. When BACE1 was activated, the cancer cells became far more aggressive in invading the brain.
BACE1 is already well-known in the neuroscience community for its role in Alzheimer’s disease. It cleaves the amyloid precursor protein (APP), initiating the formation of the sticky amyloid plaques that are a hallmark of the disease. Yet this new research shows that BACE1’s function may extend far beyond neurodegeneration.
Importantly, the study also highlights the potential to repurpose the Alzheimer’s drug Verubecestat, which targets BACE1. Although Verubecestat was discontinued in a Phase 3 Alzheimer’s trial in 2018 due to limited clinical benefit, it showed striking effects in this cancer context. Mice treated with the drug had significantly fewer and smaller brain tumors and survived longer than untreated controls.
“The discovery of BACE1 opens the door to repurposing existing treatments like Verubecestat to potentially prevent or slow the spread of lung cancer to the brain, where treatment options are currently very limited,” Singh noted.
While these findings are promising, the researchers caution that more work is needed to confirm the drug’s effectiveness and safety in human patients with brain metastases from lung cancer.
“This study highlights how interdisciplinary partnerships can lead to breakthroughs in understanding and treating devastating diseases like brain metastases,” said Dr. Shideng Bao, a cancer biologist at Cleveland Clinic and co-author of the study. “By identifying BACE1 as a key player in the spread of lung cancer to the brain, we’ve uncovered a promising new avenue for therapeutic intervention that could ultimately improve outcomes for patients.”
The research is the result of a close collaboration between McMaster University, Cleveland Clinic, and Case Comprehensive Cancer Center. The Sheila Singh Lab, internationally recognized for pioneering work in brain cancer biology, led the study. Their prior work has identified critical pathways that enable cancer cells to infiltrate the brain and escape immune detection.
The project was supported by funding from the Boris Family Fund for Brain Metastasis Research, the Canadian Cancer Society, the Canadian Institutes of Health Research, the Cancer Research UK Lung Cancer Centre of Excellence, the Cleveland Clinic Foundation and Lerner Research Institute, and a Sir Henry Wellcome Fellowship.
