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We found that activating expression of the Alzheimer\u2019s disease\u2013associated beta-secretase 1 (BACE1) led to a substantial increase in brain metastases. Furthermore, genetic and pharmacological inhibition of BACE1 blocked NSCLC brain metastasis. Mechanistically, we identified that BACE1 acts through epidermal growth factor receptor to drive this metastatic phenotype. Together, our data highlight the power of in vivo CRISPR activation screening to unveil molecular drivers and potential therapeutic targets of NSCLC brain metastasis.<\/jats:p>","DOI":"10.1126\/scitranslmed.adu2459","type":"journal-article","created":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T13:58:31Z","timestamp":1751464711000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":7,"title":["A genome-wide in vivo CRISPR activation screen identifies BACE1 as a therapeutic vulnerability of lung cancer brain metastasis"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8802-651X","authenticated-orcid":true,"given":"Shawn C.","family":"Chafe","sequence":"first","affiliation":[{"name":"Department of Surgery, McMaster University, Hamilton, ON L8S 4L8, Canada."},{"name":"Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON L8S 4L8, 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