Comparative Effects of Synthesized BACE1 and EGFR Antagonists on Lung Cancer Metastasis

Abstract

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer mortality, largely due to high rates of multi-organ metastasis and emerging drug resistance to conventional therapies. Recent findings implicate beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) in driving NSCLC brain metastasis by cleaving the extracellular domain of epidermal growth factor receptor (EGFR) and activating downstream Ras-Raf-MEK-ERK signaling. To address metastatic spread and overcome resistance, this study evaluates two newly synthesized antagonists targeting BACE1 and EGFR. The BACE1 inhibitor has reduced toxicity in the brain and-specific metastasis; the EGFR inhibitor prevents dimerization and induces lysosomal degradation to overcome resistance. Using an orthotopic immunocompromised mouse xenograft model inoculated with bioluminescent human NSCLC cells (CRUK0748-XCL-GLD), we evaluated prevention (pre-inoculation) and therapeutic (post-inoculation) regimens across brain, liver, and bone metastatic sites. BACE1 shows the most prominent early brain effects; EGFR has broader, prolonged inhibition in the liver and bone. Overall, these findings highlight dual-target inhibition of the BACE1-EGFR axis as a novel, potent, and resistance-evading strategy for comprehensive control of metastatic NSCLC.