In a groundbreaking discovery that bridges the realms of neurodegenerative disease and oncology, an international team of researchers from McMaster University, the Cleveland Clinic, and the Case Comprehensive Cancer Center has identified the protein BACE1, previously implicated almost exclusively in Alzheimer’s disease, as a pivotal factor in the spread of lung cancer to the brain. This revelation not only deepens our understanding of the complex molecular mechanisms underlying cancer metastasis but also opens promising avenues for repurposing existing drugs aimed at Alzheimer’s for the prevention of brain metastases in lung cancer patients.
Published in the esteemed journal Science Translational Medicine on July 2, 2025, this study illuminates the role of BACE1 in facilitating the invasion of lung cancer cells into the brain, a phenomenon known as brain metastasis that affects as many as 40% of individuals diagnosed with non-small cell lung cancer. Brain metastases pose a significant clinical challenge due to their aggressive progression and the scarcity of effective therapeutic options, making this discovery particularly consequential for patients facing this grim prognosis.
BACE1, or beta-site APP cleaving enzyme 1, has been extensively studied in the context of Alzheimer’s disease, where it catalyzes the cleavage of amyloid precursor protein (APP), contributing to the accumulation of amyloid plaques—hallmarks of the disease’s neurodegenerative pathology. However, by leveraging a state-of-the-art genome-wide in vivo CRISPR activation screen, the researchers systematically activated thousands of genes in lung cancer cells implanted into murine models, revealing that heightened BACE1 expression dramatically increases the propensity of these cancer cells to colonize the brain.
.adsslot_ozPBe8d6RV{width:728px !important;height:90px !important;}
@media(max-width:1199px){ .adsslot_ozPBe8d6RV{width:468px !important;height:60px !important;}
}
@media(max-width:767px){ .adsslot_ozPBe8d6RV{width:320px !important;height:50px !important;}
}
ADVERTISEMENT
The CRISPR activation screen employed is a powerful genetic screening method that allows for the selective upregulation of targeted genes across the genome in living organisms. By coupling this high-throughput approach with in vivo models that recapitulate the metastatic cascade, the scientists were able to pinpoint BACE1 as a key driver of metastatic dissemination to the brain, a finding that underscores the protein’s unexpected versatility beyond its classical role in neurodegeneration.
From a mechanistic perspective, the study suggests that BACE1 facilitates brain metastasis by manipulating molecular pathways that enable cancer cells to breach the blood-brain barrier and establish microtumors in the cerebral environment. The exact downstream effectors and substrates involved in this oncogenic hijacking remain subjects for ongoing investigation, but the identification of BACE1 shifts the paradigm, illustrating how cancer cells adopt and co-opt proteins initially characterized in unrelated diseases to overcome physiological barriers.
Crucially, this insight cross-pollinates therapeutic strategies between two historically disparate fields. The researchers focused on Verubecestat, a small molecule BACE1 inhibitor developed as an Alzheimer’s drug candidate, which had previously undergone extensive clinical trials before being discontinued due to insufficient efficacy in halting cognitive decline. By administering Verubecestat in their lung cancer mouse models, the team demonstrated a significant reduction in both the number and size of brain metastases, accompanied by prolonged survival, thereby affirming BACE1 as a targetable vulnerability in metastatic lung cancer.
The repurposing of Verubecestat for metastatic cancer prevention leverages the drug’s well-characterized pharmacological profile, potentially accelerating the translational pipeline and bypassing some of the early stages of drug development. However, the discontinuation of its Alzheimer’s trials also serves as a cautionary tale, highlighting the need for rigorous evaluation of dosing parameters, therapeutic windows, and possible side effects when redeploying this agent in oncological contexts.
Senior author Sheila Singh, a leading figure in cancer biology and director of McMaster’s Centre for Discovery in Cancer Research, emphasized how the discovery of BACE1’s role in brain metastasis exemplifies the unforeseen ways cancer exploits biological systems. This finding not only challenges the traditional compartmentalization of disease research but also exemplifies the potential of interdisciplinary collaboration to uncover novel therapeutic targets.
The study’s co-corresponding author, Shideng Bao from the Cleveland Clinic’s Department of Cancer Biology, remarked on the translational promise of identifying BACE1 as a “therapeutic vulnerability” in lung cancer brain metastasis. This points to a future where targeted therapies that inhibit metastatic processes could drastically improve clinical outcomes in patients, who currently face dismal prognoses upon detection of brain metastases.
This investigative endeavor builds on a robust foundation laid by Singh’s lab and collaborators, who have previously delineated molecular pathways exploited by cancer cells to infiltrate the brain, as well as developing innovative therapeutic approaches tailored to combat brain tumors. Their collective expertise and use of cutting-edge genomic editing tools continue to illuminate the intricate interplay between cancer pathology and the brain’s unique microenvironment.
Funding for this research was secured from esteemed organizations including the Boris Family Fund for Brain Metastasis Research, the Canadian Cancer Society, the Canadian Institute of Health Research, Cancer Research UK’s Lung Cancer Centre of Excellence, as well as institutional support from the Cleveland Clinic Foundation and Lerner Research Institute. This multi-institutional backing underscores the high priority and global interest vested in understanding and combating brain metastases.
Although the initial preclinical results are compelling, the researchers caution that further studies are required to validate the efficacy and safety of BACE1 inhibitors like Verubecestat in human patients with lung cancer brain metastases. Clinical trials will be necessary to assess pharmacodynamics, therapeutic index, and potential synergistic effects with existing cancer therapies, ultimately charting a course toward improved patient outcomes.
This pioneering research harkens to a broader trend in precision medicine, where treatment strategies are increasingly tailored by molecular profiles rather than solely anatomical origin. Targeting BACE1 represents a compelling example of how insights gleaned from one disease domain can be harnessed to innovate treatments for another, promising a future where drug repurposing accelerates the delivery of effective therapies against devastating conditions such as brain metastases arising from lung cancer.
Subject of Research: The molecular mechanisms driving lung cancer brain metastasis with a focus on the protein BACE1 and its potential as a therapeutic target.
Article Title: A genome-wide in vivo CRISPR activation screen identifies BACE1 as a therapeutic vulnerability of lung cancer brain metastasis
News Publication Date: 2-Jul-2025
Web References:
https://www.science.org/doi/10.1126/scitranslmed.adu2459
http://dx.doi.org/10.1126/scitranslmed.adu2459
Keywords: Cancer, Lung cancer, Brain metastasis, BACE1, Alzheimer’s disease, CRISPR activation screen, Verubecestat, Metastatic cancer therapy, Drug repurposing
Tags: advancements in oncologyAlzheimer’s disease connections to cancerBACE1 protein role in cancercancer metastasis mechanismsclinical implications of brain metastasesinterdisciplinary cancer researchlung cancer brain metastasismolecular biology of lung cancernon-small cell lung cancer challengesprotein interactions in cancer progressionrepurposing Alzheimer’s drugs for cancertherapeutic options for brain metastases
