Shen Zhao1, Wenfeng Fang1, Hui Pan1, Yunpeng Yang1, Ying Liang1, Lin Yang2, Xiaorong Dong3, Jianhua Zhan4, Kai Wang5, Li Zhang6. 1. Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China. 2. Department of Thoracic Surgery, Shenzhen People's Hospital, 2nd Clinical Medical College of Jinan University, Shenzhen, People's Republic of China. 3. Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. 4. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China. 5. OrigiMed Inc., Shanghai, People's Republic of China. 6. Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China. Electronic address: zhangli6@mail.sysu.edu.cn.
Abstract
INTRODUCTION: HER2 exon 20 insertion (ex20ins) is one of the most intractable problems in lung cancer. Most ex20ins are resistant to available EGFR or pan-HER tyrosine kinase inhibitors (TKIs), with the exception of a few mutants. However, the mechanism for TKI response and resistance of HER2 ex20ins remains poorly understood. METHODS: Next-generation sequencing-based genomic profiling data of 4139 patients with lung cancer were interrogated for HER2 ex20ins. Structural modeling and molecular dynamics simulations of common HER2 ex20ins were carried out to provide insights into the mechanism of activation and response heterogeneity of ex20ins. Molecular docking was performed to predict affinity to TKIs. Therapeutic decisions for patients were made on the basis of the results of genomic profiling. RESULTS: From 155 HER2-mutant lung cancer cases, Y772_A775dup and G778_P780dup were identified in 74 (47.7%) and 18 (11.6%) cases, respectively. Molecular dynamics simulations revealed that HER2 ex20ins led to ligand-independent kinase activation by changing the conformational landscape of HER2 kinase and restricting kinase conformation in the active state. G778_P780dup had a three-amino acid extension in the αC-β4 loop and retained the HER2-characteristic G776 and G778. Compared with Y772_A775dup, it had less restriction on kinase conformational sampling and higher affinity to afatinib, dacomitinib, pyrotinib, and poziotinib. Treating lung adenocarcinomas carrying G778_P780dup with these inhibitors led to sustained tumor responses in six of the 10 patients. CONCLUSIONS: The kinase conformational landscape dictated by the length of the αC-β4 loop and residues at HER2 776 and 778 position explains TKI sensitivity in ex20ins. This finding could guide therapeutic decisions with currently available therapies and future drug development strategies.
INTRODUCTION:HER2 exon 20 insertion (ex20ins) is one of the most intractable problems in lung cancer. Most ex20ins are resistant to available EGFR or pan-HER tyrosine kinase inhibitors (TKIs), with the exception of a few mutants. However, the mechanism for TKI response and resistance of HER2 ex20ins remains poorly understood. METHODS: Next-generation sequencing-based genomic profiling data of 4139 patients with lung cancer were interrogated for HER2 ex20ins. Structural modeling and molecular dynamics simulations of common HER2 ex20ins were carried out to provide insights into the mechanism of activation and response heterogeneity of ex20ins. Molecular docking was performed to predict affinity to TKIs. Therapeutic decisions for patients were made on the basis of the results of genomic profiling. RESULTS: From 155 HER2-mutant lung cancer cases, Y772_A775dup and G778_P780dup were identified in 74 (47.7%) and 18 (11.6%) cases, respectively. Molecular dynamics simulations revealed that HER2 ex20ins led to ligand-independent kinase activation by changing the conformational landscape of HER2 kinase and restricting kinase conformation in the active state. G778_P780dup had a three-amino acid extension in the αC-β4 loop and retained the HER2-characteristic G776 and G778. Compared with Y772_A775dup, it had less restriction on kinase conformational sampling and higher affinity to afatinib, dacomitinib, pyrotinib, and poziotinib. Treating lung adenocarcinomas carrying G778_P780dup with these inhibitors led to sustained tumor responses in six of the 10 patients. CONCLUSIONS: The kinase conformational landscape dictated by the length of the αC-β4 loop and residues at HER2 776 and 778 position explains TKI sensitivity in ex20ins. This finding could guide therapeutic decisions with currently available therapies and future drug development strategies.
Authors: Xiuning Le; Robin Cornelissen; Marina Garassino; Jeffrey M Clarke; Nishan Tchekmedyian; Jonathan W Goldman; Szu-Yun Leu; Gajanan Bhat; Francois Lebel; John V Heymach; Mark A Socinski Journal: J Clin Oncol Date: 2021-11-29 Impact factor: 44.544