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

Treatment of lung adenocarcinomas (LUADs) that exhibit activated epidermal growth factor receptor (EGFR) with EGFR tyrosine kinase inhibitors (TKIs) has limited efficacy. Assessment of the impact of EGFR TKI on the LUAD surfaceome remodeling reveals potential therapeutic targets. We identify 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. EGF treatment represses ALPP expression, whereas EGFR TKIs upregulate its expression through dephosphorylation and activation of FoxO3a, a transcriptional regulator that binds to the promoter region of ALPP. The combination of EGFR TKI plus ALPP antibody conjugated with monomethyl auristatin F enhances tumor killing in osimertinib-sensitive and -resistant LUAD models compared to either treatment alone. Our findings support a combination therapy involving an EGFR inhibitor together with an ALPP antibody drug conjugate for EGFR-mutated LUADs.