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Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation

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Published on: May 20, 2020

Pharmacological and Structural Characterizations of Naquotinib, a Novel Third-Generation EGFR Tyrosine Kinase

Toshiyuki Hirano¹, Hiroyuki Yasuda², Junko Hamamoto¹

¹Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, Tokyo, Japan.

Molecular Cancer Therapeutics

|February 23, 2018

Abstract:

Multiple epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKI) have been developed to effectively inhibit EGFR-derived signals in non-small cell lung cancer (NSCLC). In this study, we assessed the efficacy of EGFR-TKIs, including a novel third-generation inhibitor naquotinib (ASP8273), in clinically relevant EGFR mutations, including L858R, exon 19 deletion, L858R+T790M, exon 19 deletion+T790M with or without a C797S mutation, and several exon 20 insertion mutations. Using structural analyses, we also elucidated the mechanism of activation and sensitivity/resistance to EGFR-TKIs in EGFR exon 20 insertion mutations. The efficacy of naquotinib in cells with L858R, exon 19 deletion and exon 19 deletion+T790M was comparable with that of osimertinib. Interestingly, naquotinib was more potent than osimertinib for L858R+T790M. Additionally, naquotinib and osimertinib had comparable efficacy and a wide therapeutic window for cells with EGFR exon 20 insertions. Structural modeling partly elucidated the mechanism of activation and sensitivity/resistance to EGFR-TKIs in two EGFR exon 20 insertion mutants, A767_V769dupASV and Y764_V765insHH. In summary, we have characterized the efficacy of EGFR-TKIs for NSCLC using in vitro and structural analyses and suggested the mechanism of activation and resistance to EGFR-TKIs of EGFR exon 20 insertion mutations. Our findings should guide the selection of appropriate EGFR-TKIs for the treatment of NSCLC with EGFR mutations and help clarify the biology of EGFR exon 20 insertion mutations. Mol Cancer Ther; 17(4); 740-50. ©2018 AACR.

Insights

Naquotinib, a novel EGFR-TKI, shows efficacy comparable to osimertinib in non-small cell lung cancer (NSCLC) with common EGFR mutations. It demonstrates potent activity against L858R+T790M mutations and comparable efficacy for EGFR exon 20 insertions.

Area of Science:

Oncology
Molecular Biology
Pharmacology

Background:

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) are crucial for treating non-small cell lung cancer (NSCLC).
Emerging resistance mechanisms and novel mutations necessitate continuous development and evaluation of EGFR-TKIs.

Purpose of the Study:

To assess the efficacy of naquotinib (ASP8273), a third-generation EGFR-TKI, against various EGFR mutations in NSCLC.
To elucidate the mechanisms of activation and resistance to EGFR-TKIs in EGFR exon 20 insertion mutations using structural analyses.

Main Methods:

In vitro efficacy assessment of naquotinib and osimertinib against NSCLC cell lines harboring specific EGFR mutations (L858R, exon 19 deletion, T790M, C797S, and exon 20 insertions).
Structural analyses to understand the activation mechanisms and drug sensitivity/resistance in EGFR exon 20 insertion mutants.

Main Results:

Naquotinib demonstrated efficacy comparable to osimertinib for L858R, exon 19 deletion, and exon 19 deletion+T790M mutations.
Naquotinib showed greater potency than osimertinib against the L858R+T790M mutation.
Both naquotinib and osimertinib exhibited comparable efficacy and a wide therapeutic window for EGFR exon 20 insertion mutations.
Structural modeling provided insights into activation and resistance mechanisms for specific EGFR exon 20 insertion mutants.

Conclusions:

Naquotinib is an effective EGFR-TKI for NSCLC with various EGFR mutations, including exon 20 insertions.
Findings support naquotinib as a potential treatment option and aid in understanding EGFR exon 20 insertion mutation biology.
The study guides the selection of appropriate EGFR-TKIs for NSCLC patients with diverse EGFR alterations.

Read full analysis

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