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A genome-wide in vivo CRISPR activation screen identifies BACE1 as a therapeutic vulnerability of lung cancer brain

Shawn C Chafe1,2, Kui Zhai1,2,3, Nikoo Aghaei4

  • 1Department of Surgery, McMaster University, Hamilton, ON L8S 4L8, Canada.

Science Translational Medicine
|July 2, 2025
PubMed

Insights

Activating beta-secretase 1 (BACE1), linked to Alzheimer's disease, significantly increased brain metastases in non-small cell lung cancer (NSCLC). Inhibiting BACE1 blocked this spread, revealing a potential therapeutic target.

Area of Science:

  • Oncology
  • Neuroscience
  • Genetics

Background:

  • Brain metastasis is a frequent complication in non-small cell lung cancer (NSCLC), affecting up to 40% of patients.
  • Significant genomic differences exist between primary lung tumors and their brain metastases, with key drivers often unknown.

Purpose of the Study:

  • To identify molecular drivers of brain metastasis in non-small cell lung cancer (NSCLC).
  • To explore the role of beta-secretase 1 (BACE1) in promoting NSCLC brain metastasis.
  • To investigate BACE1 as a potential therapeutic target for NSCLC brain metastasis.

Main Methods:

  • Utilized an in vivo genome-wide CRISPR activation screen in an orthotopic xenograft model derived from an NSCLC patient.
  • Assessed the impact of gene activation on the development of brain metastases.
  • Investigated the effects of genetic and pharmacological inhibition of BACE1 on NSCLC brain metastasis.
  • Elucidated the downstream signaling pathway involving epidermal growth factor receptor (EGFR).

Main Results:

  • Activation of beta-secretase 1 (BACE1) substantially increased the incidence of brain metastases in the NSCLC model.
  • Genetic and pharmacological inhibition of BACE1 effectively blocked NSCLC brain metastasis.
  • BACE1 was found to mediate its pro-metastatic effects through the epidermal growth factor receptor (EGFR) pathway.

Conclusions:

  • In vivo CRISPR activation screening is a powerful tool for discovering metastasis drivers.
  • Beta-secretase 1 (BACE1) is a key molecular driver of non-small cell lung cancer (NSCLC) brain metastasis.
  • Targeting BACE1, potentially in combination with EGFR pathways, offers a promising therapeutic strategy for NSCLC brain metastasis.

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