Lung Adenocarcinoma Surfaceome Remodeling With Egfr Inhibitors Uncovers Placental Alkaline Phosphatase as a Target for Combination Therapy

Authors

Yihui Chen
Rongzhang Dou
Monica J Hong
Hanwen Xu
Jody Vykoukal
Ricardo A León-Letelier
Yining Cai
Soyoung Park
Ehsan Irajizad
Fu Chung Hsiao
Jennifer B Dennison
Edwin J Ostrin
Johannes F Fahrmann
Hiroyuki Katayama
Samir M Hanash

Language

English

Publication Date

12-16-2025

Journal

Cell Reports Medicine

DOI

10.1016/j.xcrm.2025.102513

PMID

41406940

PMCID

PMC12765945

PubMedCentral® Posted Date

12-16-2025

PubMedCentral® Full Text Version

Post-print

Abstract

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.

Keywords

Humans, ErbB Receptors, Adenocarcinoma of Lung, Protein Kinase Inhibitors, Lung Neoplasms, Alkaline Phosphatase, Animals, Cell Line, Tumor, GPI-Linked Proteins, Mice, Forkhead Box Protein O3, Female, Drug Resistance, Neoplasm, Mice, Nude, Gene Expression Regulation, Neoplastic, Isoenzymes, lung adenocarcinomas, EGFR, placental-type alkaline phosphatase, antibody drug conjugate

Published Open-Access

yes

Recommended Citation

Chen, Yihui; Dou, Rongzhang; Hong, Monica J; et al., "Lung Adenocarcinoma Surfaceome Remodeling With Egfr Inhibitors Uncovers Placental Alkaline Phosphatase as a Target for Combination Therapy" (2025). Faculty, Staff and Student Publications. 6370.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6370