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Conformational Landscapes of HER2 Exon 20 Insertions Explain Their Sensitivity to Kinase Inhibitors in Lung
Shen Zhao1, Wenfeng Fang1, Hui Pan1
1Department 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.
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.
Insights
HER2 exon 20 insertions (ex20ins) in lung cancer are often resistant to TKIs. Specific HER2 ex20ins mutations influence TKI sensitivity by altering kinase conformation, guiding treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- HER2 exon 20 insertions (ex20ins) represent a significant challenge in lung cancer treatment due to inherent resistance to most tyrosine kinase inhibitors (TKIs).
- The precise mechanisms underlying TKI response and resistance in HER2 ex20ins remain incompletely understood, hindering effective therapeutic strategies.
Purpose of the Study:
- To investigate the structural and mechanistic basis for TKI sensitivity and resistance in HER2 ex20ins lung cancer.
- To correlate specific HER2 ex20ins mutations with differential responses to available TKIs.
Main Methods:
- Genomic profiling of 4139 lung cancer patients to identify HER2 ex20ins.
- Utilized structural modeling and molecular dynamics simulations to analyze HER2 ex20ins activation and TKI binding.
- Performed molecular docking to predict drug-target interactions.
Main Results:
- Identified Y772_A775dup and G778_P780dup as common HER2 ex20ins, occurring in 47.7% and 11.6% of cases, respectively.
- Demonstrated that HER2 ex20ins promote ligand-independent kinase activation by stabilizing the active conformation.
- G778_P780dup exhibited higher affinity to afatinib, dacomitinib, pyrotinib, and poziotinib, leading to sustained responses in 6/10 patients.
Conclusions:
- The conformational landscape of HER2 kinase, influenced by the αC-β4 loop and specific residues, dictates TKI sensitivity in ex20ins.
- These findings provide a mechanistic basis for guiding TKI selection in HER2 ex20ins lung cancer and inform future drug development.
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