B7‐H3‐Induced Signaling in Lung Adenocarcinoma Cell Lines with Divergent Epidermal Growth Factor Receptor Mutation Patterns
Meng Ding, Haixiu Liao, Nannan Zhou, Ying Yang, Shihe Guan, Liwen Chen
Abstract
The cosignal molecule B7‐H3 is gaining attention due to its abnormal expression and abundant signal transduction in many types of malignancies. B7‐H3‐induced signaling includes at least three cascades: PI3K/AKT, JAK2/STAT3, and Raf/MEK/ERK1/2, which are also involved in epidermal growth factor receptor‐ (EGFR‐) triggered signaling in lung adenocarcinoma cells. However, the correlation between B7‐H3‐induced signaling and EGFR signaling, and between B7‐H3‐targeted immunotherapy and EGFR‐targeted therapy in lung adenocarcinoma, remains to be elucidated. Herein we find that knockout of B7-H3 gene decreased cell survival and increased EGFR‐tyrosine kinase inhibitor gefitinib susceptibility of both H3255 and HCC827 cells, two lung adenocarcinoma cell lines harboring EGFR L858R (exon 21) and Del E746‐A750 (exon 19) mutations, respectively. B7-H3 deletion resulted in dramatic reduction of phosphorylation level of AKT and STAT3 in H3255 cells while having mild‐to‐moderate suppression on AKT, STAT3, and ERK1/2 in HCC827 cells. Gefitinib had similar effects with B7-H3 deletion both in H3255 and HCC827 cells. Furthermore, B7-H3 ablation had significant synergistic effects with gefitinib in HCC827 cells. Collectively, our study reveals B7‐H3‐induced signaling in lung adenocarcinoma cell lines with divergent EGFR mutations, and a translational potential of combined targeted therapy of B7‐H3 and EGFR in lung adenocarcinoma with EGFR Del E746‐A750 mutation.