Structural basis for the altered drug sensitivities of non-small cell lung cancer-associated mutants of human epidermal growth factor receptor
Abstract
The epidermal growth factor receptor (EGFR) has an essential role in multiple signaling pathways, including cell proliferation and migration, through extracellular ligand binding and subsequent activation of its intracellular tyrosine kinase (TK) domain. The non-small cell lung cancer (NSCLC)-associated EGFR mutants, L858R and G719S, are constitutively active and oncogenic. They display sensitivity to TK inhibitors, including gefitinib and erlotinib. In contrast, the secondary mutation of the gatekeeper residue, T790M, reportedly confers inhibitor resistance on the oncogenic EGFR mutants. In this study, our biochemical analyses revealed that the introduction of the T790M mutation confers gefitinib resistance on the G719S mutant. The G719S/T790M double mutant has enhanced activity and retains high gefitinib-binding affinity. The T790M mutation increases the ATP affinity of the G719S mutant, explaining the acquired drug resistance of the double mutant. Structural analyses of the G719S/T790M double mutant, as well as the wild type and the G719S and L858R mutants, revealed that the T790M mutation stabilizes the hydrophobic spine of the active EGFR-TK conformation. The Met790 side chain of the G719S/T790M double mutant, in the apo form and gefitinib- and AMPPNP-bound forms, adopts different conformations that explain the accommodation of these ligands. In the L858R mutant structure, the active-site cleft is expanded by the repositioning of Phe723 within the P-loop. Notably, the introduction of the F723A mutation greatly enhanced the gefitinib sensitivity of the wild-type EGFR in vivo, supporting our hypothesis that the expansion of the active-site cleft results in enhanced gefitinib sensitivity. Taken together, our results provide a structural basis for the altered drug sensitivities caused by distinct NSCLC-associated EGFR mutations.
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Patients with atypical EGFR mutations show heterogeneous and reduced responses to EGFR inhibitors, including osimertinib.
“Patients with atypical EGFR mutations show heterogeneous and reduced responses to EGFR inhibitors1,3,7–10, including osimertinib12.”
From Structure-based classification predicts drug response in EGFR-mutant NSCLC (2021) · cites this paper as [7]
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Structure-based classification predicts drug response in EGFR-mutant NSCLC
Robichaux, J. P., Le, X., Vijayan, R. S. K., Hicks, J. K., Heeke, S., Elamin, Y. Y., Lin, H. Y., Udagawa, H., Skoulidis, F., Tran, H., et al. (2021) · Nature · doi:10.1038/s41586-021-03898-1 · Cited by 490 · see citing works
- Authors
- Yoshikawa, S., Kukimoto-Niino, M., Parker, L., Handa, N., Terada, T., Fujimoto, T., Terazawa, Y., Wakiyama, M., Sato, M., Sano, S., Kobayashi, T., Tanaka, T., Chen, L., Liu, Z.-J., Wang, B.-C., Shirouzu, M., Kawa, S., Semba, K., Yamamoto, T., & Yokoyama, S.
- Affiliations
- RIKEN (JP)
- Japan Aerospace Exploration Agency (JP)
- University of Georgia (US)
- Institute of Medical Science, The University of Tokyo (JP)
- Waseda University (JP)
- Okinawa Institute of Science and Technology Graduate University (JP)
- Corresponding author
- Yamamoto, T
- Yokoyama, S
- Venue
- Oncogene
- Published
- 2012-02-20
- Volume
- 32
- Issue
- 1
- Pages
- 27-38
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2167270950
- Cited by
- 138
- References
- 47
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 8 · 2023: 8 · 2022: 11 · 2021: 13 · 2020: 10 · 2019: 9 · 2018: 2 · 2017: 15 · 2016: 13 · 2015: 14 · 2014: 9 · 2013: 6 · 2012: 5
- FWCI
- 9.01
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- DORA PSI (Paul Scherrer Institute) (submittedVersion)
- Funders
- European Space Agency
- Universidad de Granada
- Japan Society for the Promotion of Science (21229006)
- Japan Aerospace Exploration Agency
- RIKEN
- Basic Energy Sciences
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- epidermal growth factor receptor, EGFR mutation, non-small cell lung cancer, gefitinib resistance, T790M mutation, L858R mutation, tyrosine kinase inhibitors, drug resistance, ATP affinity, active site cleft
- MeSH terms
- Gefitinib, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Drug Screening Assays, Antitumor, Humans, Lung Neoplasms, Mutation, Protein Conformation, Protein-Tyrosine Kinases, Quinazolines, ErbB Receptors
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