Lung adenocarcinoma surfaceome remodeling with EGFR inhibitors uncovers placental alkaline phosphatase as a target for combination therapy

Treatment of lung adenocarcinomas (LUAD) that exhibit activated epidermal growth factor receptor (EGFR) with EGFR tyrosine kinase inhibitors (TKI) has limited efficacy. Assessment of the impact of EGFR TKI on the LUAD surfaceome remodeling revealed potential therapeutic targets. We identified placental type alkaline phosphatase (ALPP) which has restricted expression in normal tissues, among upregulated surface proteins following EGFR TKI treatment of both TKI sensitive as well as resistant cells. Upregulation of ALPP with EGFR TKI resulted from activation of FoxO3a. The combination of EGFR TKI plus ALPP antibody conjugated with monomethylauristatin F enhanced tumor killing in osimertinib-sensitive and osimertinib-resistant LUAD models compared to either treatment alone. Our findings point to surfaceome remodeling induced with an established cancer therapy as a means for the development of more effective combination therapies.