Molecular determinants of drug-specific sensitivity for epidermal growth factor receptor (EGFR) exon 19 and 20 mutants in non-small cell lung cancer
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// Igor F. Tsigelny 1,2,3 , Jennifer J. Wheler 4 , Jerry P. Greenberg 2 , Valentina L. Kouznetsova 1,2 , David J. Stewart 5 , Lyudmila Bazhenova 1 and Razelle Kurzrock 1 1 Center for Personalized Cancer Therapy, Moores UCSD Cancer Center, La Jolla, CA, USA 2 San Diego Supercomputer Center, University of California, San Diego, La Jolla, CA, USA 3 Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA 4 M.D. Anderson Cancer Center, University of Texas, Houston, TX, USA 5 Department of Medicine, University of Ottawa, Ottawa, Canada Correspondence to: Igor F. Tsigelny, email: // Razelle Kurzrock, email: // Keywords : EGFR, adenocarcinoma, lung cancer, reversible TKI inhibitors, irreversible TKI inhibitors Received : December 04, 2014 Accepted : January 21, 2015 Published : February 28, 2015 Abstract We hypothesized that aberrations activating epidermal growth factor receptor (EGFR) via dimerization would be more sensitive to anti-dimerization agents (e.g., cetuximab). EGFR exon 19 abnormalities (L747_A750del; deletes amino acids LREA) respond to reversible EGFR kinase inhibitors (TKIs). Exon 20 in-frame insertions and/or duplications (codons 767 to 774) and T790M mutations are clinically resistant to reversible/some irreversible TKIs. Their impact on protein function/therapeutic actionability are not fully elucidated. In our study, the index patient with non-small cell lung cancer (NSCLC) harbored EGFR D770_P772del_insKG (exon 20). A twenty patient trial (NSCLC cohort) (cetuximab-based regimen) included two participants with EGFR TKI-resistant mutations ((i) exon 20 D770>GY; and (ii) exon 19 LREA plus exon 20 T790M mutations). Structural modeling predicted that EGFR exon 20 anomalies (D770_P772del_insKG and D770>GY), but not T790M mutations, stabilize the active dimer configuration by increasing the interaction between the kinase domains, hence sensitizing to an agent preventing dimerization. Consistent with predictions, the two patients harboring D770_P772del_insKG and D770>GY, respectively, responded to an EGFR antibody (cetuximab)-based regimen; the T790M-bearing patient showed no response to cetuximab combined with erlotinib. In silico modeling merits investigation of its ability to optimize therapeutic selection based on structural/functional implications of different aberrations within the same gene.
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In previously published clinical studies, patients with only a single amino acid insertion responded better to already-established therapies, such as erlotinib plus cetuximab or irreversible inhibitors, compared to patients with larger insertions comprised of three amino acids.
“In previously published clinical studies, patients with only a single amino acid insertion responded better to already-established therapies, such as erlotinib plus cetuximab or irreversible inhibitors, compared to patients with larger insertions comprised of three amino acids48,49,50.”
From Mechanisms and clinical activity of an EGFR and HER2 exon 20–selective kinase inhibitor in non–small cell lung cancer (2018) · cites this paper as [48]
Exon 20 mutations (EGFR D770_P772del_insKG and D770>GY), intrinsically associated with resistance to EGFR TKIs, activate EGFR by increasing attractive electrostatic dimerization energies.
“Moreover, it was demonstrated that exon 20 mutations (EGFR D770_P772del_insKG and D770 > GY), which are intrinsically associated with resistance to EGFR TKIs, activate EGFR by increasing the attractive electrostatic dimerization energies.”
From A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): Old successes and future perspectives (2015) · cites this paper as [106]
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- Authors
- Tsigelny, I. F., Wheler, J. J., Greenberg, J. P., Kouznetsova, V. L., Stewart, D. J., Bazhenova, L., & Kurzrock, R.
- Affiliations
- San Diego Supercomputer Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- University of Ottawa (CA)
- University of California San Diego (US)
- ORCID
- Venue
- Oncotarget
- Publisher
- Impact Journals, LLC
- Published
- 2015-02-28
- Volume
- 6
- Issue
- 8
- Pages
- 6029-6039
- ISSN
- 1949-2553 (ISSN-L)
- PMC
- PMC4467419
- OpenAlex
- W1884843684
- Cited by
- 30
- References
- 39
- Citations by year
- 2023: 1 · 2022: 5 · 2021: 5 · 2020: 3 · 2019: 3 · 2018: 2 · 2017: 2 · 2016: 5 · 2015: 4
- FWCI
- 3.43
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- cc-by
- Locations
- Oncotarget (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- 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 › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- EGFR, non-small cell lung cancer, exon 19 deletion, exon 20 insertion, T790M mutation, cetuximab, EGFR kinase inhibitors, drug resistance, EGFR dimerization, EGFR tyrosine kinase, structural modeling, targeted therapy
- MeSH terms
- Adult, Aged, Carcinoma, Non-Small-Cell Lung, Exons, Humans, Lung Neoplasms, Male, Models, Molecular, Mutation, ErbB Receptors
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