Specific HER2 Exon 20 Gly776 Deletion-Insertions in Non-Small Cell Lung Cancer: Structural Analysis and Sensitivity to HER2-Targeted Tyrosine Kinase Inhibitors.

Guangjian Yang,Junling Li,Haiyan Xu,Yan Wang,Jiaqi Hu,Xuezhi Hao,Peizeng Hu,Yaning Yang,Fei Xu,Weihua Li,Xin Ai,Runze Liu,Shuyang Zhang

doi:10.3389/fphar.2022.806737

Abstract

Background: HER2 exon 20 insertions remain a subset heterogeneous alterations in lung cancer, with currently unmet need for precision targeted therapy. G776delinsVC, a typical HER2 exon 20 deletion-insertion at codon Gly776, was reported to respond discrepantly to afatinib compared with the predominant insertion A775_G776insYVMA (YVMA). However, it lacks structural evidence to illustrate the possible mechanism and predict the binding activities of its similar variants over YVMA insertion to HER2-targered tyrosine kinase inhibitors (TKIs). Methods: Real-world cohort study was performed to investigate clinical outcomes with HER2-targeted TKI afatinib and pyrotinib, and structural analysis for exon 20 Gly776 deletion-insertions G776delinsVC, G776delinsLC and G776delinsVV, and YVMA by molecular dynamics simulation and cellular kinase inhibition assay were provided for full exploration. Results: Afatinib revealed low objective response rate (ORR) of 0–9.5% and short median progression-free survival (mPFS) of 2.8–3.2 months for YVMA, but with higher ORR of 20–28.6% and longer mPFS of 4.3–7.1 months for G776delinsVC. Pyrotinib presented significantly improved PFS benefit than afatinib for G776delinsVC and YVMA as first-line (median, 6.8 vs. 3.4 months, p = 0.010) or second-line therapy (median, 5.8 vs. 2.8 months, p < 0.001). No significant difference was observed on drug binding pocket and TKI binding activity between G776delinsVC, G776delinsLC and G776delinsVV, and both afatinib and pyrotinib showed favorable binding activity. YVMA insertion significantly affected the loop region with altering HER2 protein secondary structure and forming steric hindrance to binding of afatinib. Pyrotinib showed the best selectivity to HER2, with more favorable activity to YVMA than afatinib indicated by cellular inhibition assay. Conclusion: Both afatinib and pyrotinib showed favorable activity for NSCLC patients with HER2 exon 20 Gly776 deletion-insertions. Pyrotinib revealed more potent activity to A775_G776insYVMA insertion than afatinib due to the steric binding hindrance induced by YVMA.

Highlights

Activating alterations of human epidermal growth factor receptor 2 (HER2, known as ERBB2), a member of the ErbB receptor tyrosine kinase family, have been identified as oncogenic drivers, occurring in 2–4% in non-small cell lung cancer (NSCLC) (Stephens et al, 2004; Arcila et al, 2012; Mazières et al, 2013; Peters and Zimmermann, 2014; Kris et al, 2015)
A total of 172 eligible patients with metastatic or recurrent lung adenocarcinoma who received chemotherapy, immune checkpoint inhibitors or tyrosine kinase inhibitor (TKI) were screened in this study
We identified the specific HER2 exon 20 glycine at codon 776 (Gly776) deletion-insertion variants could be as potential genomic modifiers of response to afatinib targeted therapy

Summary

Introduction

Activating alterations of human epidermal growth factor receptor 2 (HER2, known as ERBB2), a member of the ErbB receptor tyrosine kinase family, have been identified as oncogenic drivers, occurring in 2–4% in non-small cell lung cancer (NSCLC) (Stephens et al, 2004; Arcila et al, 2012; Mazières et al, 2013; Peters and Zimmermann, 2014; Kris et al, 2015). Several studies had reported response heterogeneities to HER2-targeted tyrosine kinase inhibitor (TKI) afatinib among HER2 ex20ins (De Grève et al, 2012; Liu et al, 2018; Nagano et al, 2018; Dziadziuszko et al, 2019; Lai et al, 2019). Afatinib was reported with significantly improved mPFS for non-YVMA insertions (G778_P780dup and G776delinsVC) compared with YVMA (7.6 vs 1.2 months, p < 0.001), in which no response (ORR, 0/14) was observed in patients with YVMA (Kosaka et al, 2017; Fang et al, 2020). These studies revealed that YVMA insertion showed relatively much lower response to afatinib than other HER2 ex20ins variants. It lacks structural evidence to illustrate the possible mechanism and predict the binding activities of its similar variants over YVMA insertion to HER2-targered tyrosine kinase inhibitors (TKIs)

Methods

Results

Conclusion