The DOI matches its Crossref record; 15 of the 15 references it cites were found in a registry or an index.
EGFR Exon 18 Mutations in Lung Cancer: Molecular Predictors of Augmented Sensitivity to Afatinib or Neratinib as Compared with First- or Third-Generation TKIs
Published version of a preprint
Abstract
Purpose: Lung cancers harboring common EGFR mutations respond to EGFR tyrosine kinase inhibitors (TKI), whereas exon 20 insertions (Ins20) are resistant to them. However, little is known about mutations in exon 18. Experimental Design: Mutational status of lung cancers between 2001 and 2015 was reviewed. Three representative mutations in exon 18, G719A, E709K, and exon 18 deletion (Del18: delE709_T710insD) were retrovirally introduced into Ba/F3 and NIH/3T3 cells. The 90% inhibitory concentrations (IC90s) of first-generation (1G; gefitinib and erlotinib), second-generation (2G; afatinib, dacomitinib, and neratinib), and third-generation TKIs (3G; AZD9291 and CO1686) were determined. Results: Among 1,402 EGFR mutations, Del19, L858R, and Ins20 were detected in 40%, 47%, and 4%, respectively. Exon 18 mutations, including G719X, E709X, and Del18, were present in 3.2%. Transfected Ba/F3 cells grew in the absence of IL3, and NIH/3T3 cells formed foci with marked pile-up, indicating their oncogenic abilities. IC90s of 1G and 3G TKIs in G719A, E709K, and Del18 were much higher than those in Del19 (by >11–50-fold), whereas IC90s of afatinib were only 3- to 7-fold greater than those for Del19. Notably, cells transfected with G719A and E709K exhibited higher sensitivity to neratinib (by 5–25-fold) than those expressing Del19. Patients with lung cancers harboring G719X exhibited higher response rate to afatinib or neratinib (∼80%) than to 1G TKIs (35%–56%) by compilation of data in the literature. Conclusions: Lung cancers harboring exon 18 mutations should not be overlooked in clinical practice. These cases can be best treated with afatinib or neratinib, although the currently available in vitro diagnostic kits cannot detect all exon 18 mutations. Clin Cancer Res; 21(23); 5305–13. ©2015 AACR.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Epidermal growth factor receptor (EGFR) mutations typically occur in exons 18–21 and are established driver mutations in non-small cell lung cancer (NSCLC)1–3.”
From Structure-based classification predicts drug response in EGFR-mutant NSCLC (2021) · cites this paper as [2]
In the citing paper
“Preclinical studies have demonstrated an augmented sensitivity of exon 18 mutations to second-generation irreversible EGFR TKIs (i.e., afatinib and neratinib) in comparison to first- or third-generation inhibitors [30].”
In the citing paper
“G719A is more sensitive to second-generation EGFR TKIs than first- or third-generation agents [30].”
In the citing paper
“Preclinical studies have shown that these mutations are oncogenic and are sensitive to EGFR TKI, although they display different sensitivity profiles to these agents.”
In the citing paper
“Preclinical studies suggest that they are the least sensitive exon 18 mutations to the different classes of EGFR TKIs”
In the citing paper
“having greater IC90s (>25-fold) with erlotinib, gefitinib, and osimertinib in cells transfected with E709K than those with exon 19 deletions, but no IC90s differences with afatinib or neratinib [30].”
In the citing paper
“Exon 18 mutations collectively account for approximately 3–4% of all EGFR mutations”
In the citing paper
“In preclinical models, these mutations have been associated with less sensitivity to EGFR TKIs, compared with G719X point mutations.”
In the citing paper
“include point mutations, which, in >80% of cases, involve the codons 719 (G719X and the most common variants, G719A, G719S, and G719C) or 709 (E709X), and more rarely, deletion–insertions [19,29,30].”
In the citing paper
“In preclinical studies, the L861Q mutation is resistant to fi rst-generation TKIs, whereas it might be sensitive to afatinib or osimertinib. 28-31”
From Osimertinib for Patients With Non–Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Multicenter, Open-Label, Phase II Trial (KCSG-LU15-09) (2020) · cites this paper as [29]
In the citing paper
“In contrast, our previous study, in which the sensitivities to various EGFR‐TKI for exon 18 mutations were investigated in vitro, showed the efficacy of afatinib or neratinib against exon 18 mutations.”
In the citing paper
“Our previous in vitro study has demonstrated the efficacy of afatinib or neratinib for the exon 18 mutation, including G719X.27”
In the citing paper
“Our previous study has shown that EGFR exon 18 mutations are less sensitive to 1G EGFR‐TKI, compared with common mutations,27”
In the citing paper
“Preclinical studies showing a lower efficacy of 1G EGFR‐TKI for such uncommon mutations supports these clinical data.27, 41, 42, 43”
In the citing paper
“the Ba/F3 cell line has often been used in many studies investigating EGFR mutations,24, 27, 36, 41, 42”
In the citing paper
“Our previous in vitro study showed a lower efficacy of 3G EGFR‐TKI, including osimertinib, for EGFR exon 18 mutations,27”
In the citing paper
“We recently reported that second generation EGFR‐TKI, afatinib or neratinib, are especially effective for EGFR exon 18 mutations compared with other EGFR‐TKI, indicating the significance of mutation‐specific EGFR‐TKI selection.16”
From Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy (2016) · cites this paper as [16]
In the citing paper
“Del19 and L858R account for 44.8% (2573/5741) and 39.8% (2283/5741) of EGFR mutations, respectively.29, 45, 46, 47, 48”
From Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy (2016) · cites this paper as [29]
In the citing paper
“G719A, E709K and Del18 appeared to have high sensitivity to afatinib or neratinib compared to 1G or 3G‐TKI in our in vitro study.29”
From Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy (2016) · cites this paper as [29]
In the citing paper
“These genotypes are present in 3.1% (100/3186), 0.3% (9/3186) and 0.3% (9/3186), respectively (Fig. 1).29, 61, 69”
From Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy (2016) · cites this paper as [29]
In the citing paper
“ORR to 1G‐TKI in patients with G719X‐tumors as a single mutation and Del18 were only 32% and 25%, respectively (Table 3).29, 61, 69, 70, 71, 72, 73”
From Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy (2016) · cites this paper as [29]
In the citing paper
“In addition, two out of four patients with tumors harboring E709X+G719X or L858R, as well as our patient with Del18‐tumor, achieved partial responses to afatinib after the treatment with 1G‐TKI.29, 74”
From Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy (2016) · cites this paper as [29]
In the citing paper
“ORR to 1G‐TKI in S768I and L861Q tumors were only 42 and 39%, respectively (Table 3).26, 29, 61, 69, 70, 71, 72, 73, 75, 76, 77, 78, 79, 80”
From Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy (2016) · cites this paper as [29]
Citations
Cites
Gefitinib or Chemotherapy for Non–Small-Cell Lung Cancer with Mutated EGFR
Maemondo, M., Inoue, A., Kobayashi, K., Sugawara, S., Oizumi, S., Isobe, H., Gemma, A., Harada, M., Yoshizawa, H., Kinoshita, I., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa0909530 · Cited by 5,525
Rosell, R., Carcereny, E., Gervais, R., Vergnenegre, A., Massuti, B., Felip, E., Palmero, R., Garcia-Gomez, R., Pallares, C., Sanchez, J. M., et al. (2012) · The Lancet Oncology · doi:10.1016/s1470-2045(11)70393-x · Cited by 5,489
Mitsudomi, T., Morita, S., Yatabe, Y., Negoro, S., Okamoto, I., Tsurutani, J., Seto, T., Satouchi, M., Tada, H., Hirashima, T., et al. (2010) · The Lancet Oncology · doi:10.1016/s1470-2045(09)70364-x · Cited by 4,090
Self-citationPao, W., Miller, V. A., Politi, K. A., Riely, G. J., Somwar, R., Zakowski, M. F., Kris, M. G., & Varmus, H. (2005) · PLoS Medicine · doi:10.1371/journal.pmed.0020073 · Cited by 3,527
Sequist, L. V., Yang, J. C.-H., Yamamoto, N., O'Byrne, K., Hirsh, V., Mok, T., Geater, S. L., Orlov, S., Tsai, C.-M., Boyer, M., et al. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.44.2806 · Cited by 3,228
Comprehensive analysis of kinase inhibitor selectivity
Davis, M. I., Hunt, J. P., Herrgard, S., Ciceri, P., Wodicka, L. M., Pallares, G., Hocker, M., Treiber, D. K., & Zarrinkar, P. P. (2011) · Nature Biotechnology · doi:10.1038/nbt.1990 · Cited by 2,409
Wu, Y.-L., Zhou, C., Hu, C.-P., Feng, J., Lu, S., Huang, Y., Li, W., Hou, M., Shi, J. H., Lee, K. Y., et al. (2014) · The Lancet Oncology · doi:10.1016/s1470-2045(13)70604-1 · Cited by 1,978
Using Multiplexed Assays of Oncogenic Drivers in Lung Cancers to Select Targeted Drugs
Kris, M. G., Johnson, B. E., Berry, L. D., Kwiatkowski, D. J., Iafrate, A. J., Wistuba, I. I., Varella-Garcia, M., Franklin, W. A., Aronson, S. L., Su, P.-F., et al. (2014) · JAMA · doi:10.1001/jama.2014.3741 · Cited by 1,724
Yang, J. C.-H., Wu, Y.-L., Schuler, M., Sebastian, M., Popat, S., Yamamoto, N., Zhou, C., Hu, C.-P., O'Byrne, K., Feng, J., et al. (2015) · The Lancet Oncology · doi:10.1016/s1470-2045(14)71173-8 · Cited by 1,574 · cited 1×
“The LUX-lung 3 and 6 studies, which compared afatinib to platinum doublet chemotherapy, showed a survival benefit of afatinib for patients with tumors harboring Del 19 but not for patients with L858R-mutant tumors, which suggested that even these common mutations have different chemosensitivities (35).”
BackgroundYang, J. C.-H., Sequist, L. V., Geater, S. L., Tsai, C.-M., Mok, T. S. K., Schuler, M., Yamamoto, N., Yu, C.-J., Ou, S.-H. I., Zhou, C., et al. (2015) · The Lancet Oncology · doi:10.1016/s1470-2045(15)00026-1 · Cited by 1,002
Research works printed but not linked: 20
- Yatabe, 2015, EGFR mutation testing practices within the Asia Pacific region: results of a multicenter diagnostic survey, J Thorac Oncol, 10, 438, 10.1097/JTO.0000000000000422 · DOI · Paper page
- Zhou, 2011, Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study, Lancet Oncol, 12, 735, 10.1016/S1470-2045(11)70184-X · DOI · Paper page
- Wu, 2008, Lung cancer with epidermal growth factor receptor exon 20 mutations is associated with poor gefitinib treatment response, Clin Cancer Res, 14, 4877, 10.1158/1078-0432.CCR-07-5123 · DOI · Paper page
- Kobayashi, 2005, EGFR mutation and resistance of non-small-cell lung cancer to gefitinib, N Engl J Med, 352, 786, 10.1056/NEJMoa044238 · DOI · Paper page
- Gow, 2005, Acquired gefitinib-resistant mutation of EGFR in a chemonaive lung adenocarcinoma harboring gefitinib-sensitive mutation L858R, PLoS Med, 2, e269, 10.1371/journal.pmed.0020269 · DOI
- Shi, 2014, A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER), J Thorac Oncol, 9, 154, 10.1097/JTO.0000000000000033 · DOI
- Chiu, 2015, Epidermal growth factor receptor tyrosine kinase inhibitor treatment response in advanced lung adenocarcinomas with G719X/L861Q/S768I mutations, J Thorac Oncol, 10, 793, 10.1097/JTO.0000000000000504 · DOI · Paper page
- Kosaka, 2004, Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications, Cancer Res, 64, 8919, 10.1158/0008-5472.CAN-04-2818 · DOI
- Mitsudomi, 2005, Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence, J Clin Oncol, 23, 2513, 10.1200/JCO.2005.00.992 · DOI
- Yatabe, 2006, A rapid, sensitive assay to detect EGFR mutation in small biopsy specimens from lung cancer, J Mol Diagn, 8, 335, 10.2353/jmoldx.2006.050104 · DOI
- Yatabe, 2011, Heterogeneous distribution of EGFR mutations is extremely rare in lung adenocarcinoma, J Clin Oncol, 29, 2972, 10.1200/JCO.2010.33.3906 · DOI
- Sogabe, 2014, MEK inhibitor for gastric cancer with MEK1 gene mutations, Mol Cancer Ther, 13, 3098, 10.1158/1535-7163.MCT-14-0429 · DOI
- Tanaka, 2009, SRPX2 is overexpressed in gastric cancer and promotes cellular migration and adhesion, Int J Cancer, 124, 1072, 10.1002/ijc.24065 · DOI
- Nakagawa, 2003, Phase I pharmacokinetic trial of the selective oral epidermal growth factor receptor tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839) in Japanese patients with solid malignant tumors, Ann Oncol, 14, 922, 10.1093/annonc/mdg250 · DOI
- Hidalgo, 2001, Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies, J Clin Oncol, 19, 3267, 10.1200/JCO.2001.19.13.3267 · DOI · Paper page
- Janne, 2015, AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer, N Engl J Med, 372, 1689, 10.1056/NEJMoa1411817 · DOI · Paper page
- Sequist, 2010, Neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor: results of a phase II trial in patients with advanced non-small-cell lung cancer, J Clin Oncol, 28, 3076, 10.1200/JCO.2009.27.9414 · DOI
- Wu, 2011, Effectiveness of tyrosine kinase inhibitors on “uncommon” epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer, Clin Cancer Res, 17, 3812, 10.1158/1078-0432.CCR-10-3408 · DOI · Paper page
- Ackerman, 2012, EGFR delE709_T710insD: a rare but potentially EGFR inhibitor responsive mutation in non-small-cell lung cancer, J Thorac Oncol, 7, e19, 10.1097/JTO.0b013e3182635ab4 · DOI
- Drilon, 2015, Broad, hybrid capture-based next-generation sequencing identifies actionable genomic alterations in “driver-negative” lung adenocarcinomas, Clin Cancer Res, 10.1158/1078-0432.CCR-14-2683 · DOI · Paper page
Cited by
Sorted by citations
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
Kobayashi, Y., & Mitsudomi, T. (2016) · Cancer Science · doi:10.1111/cas.12996 · Cited by 413
Self-citationCho, J. H., Lim, S. H., An, H. J., Kim, K. H., Park, K. U., Kang, E. J., Choi, Y. H., Ahn, M. S., Lee, M. H., Sun, J.-M., et al. (2020) · Journal of Clinical Oncology · doi:10.1200/jco.19.00931 · Cited by 358
Yu, H. A., Suzawa, K., Jordan, E., Zehir, A., Ni, A., Kim, R., Kris, M. G., Hellmann, M. D., Li, B. T., Somwar, R., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-2961 · Cited by 259
Kohsaka, S., Nagano, M., Ueno, T., Suehara, Y., Hayashi, T., Shimada, N., Takahashi, K., Suzuki, K., Takamochi, K., Takahashi, F., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aan6566 · Cited by 210
Aisner, D. L., Sholl, L. M., Berry, L. D., Rossi, M. R., Chen, H., Fujimoto, J., Moreira, A. L., Ramalingam, S. S., Villaruz, L. C., Otterson, G. A., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-2289 · Cited by 206
Courtney, K. D., Ma, Y., Diaz de Leon, A., Christie, A., Xie, Z., Woolford, L., Singla, N., Joyce, A., Hill, H., Madhuranthakam, A. J., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-1459 · Cited by 188
Russo, A., Franchina, T., Ricciardi, G., Battaglia, A., Picciotto, M., & Adamo, V. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20061431 · Cited by 110
Shen, Y.-C., Tseng, G.-C., Tu, C.-Y., Chen, W.-C., Liao, W.-C., Chen, W.-C., Li, C.-H., Chen, H.-J., & Hsia, T.-C. (2017) · Lung Cancer · doi:10.1016/j.lungcan.2017.06.007 · Cited by 99
TAS6417, A Novel EGFR Inhibitor Targeting Exon 20 Insertion Mutations
Hasako, S., Terasaka, M., Abe, N., Uno, T., Ohsawa, H., Hashimoto, A., Fujita, R., Tanaka, K., Okayama, T., Wadhwa, R., et al. (2018) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-17-1206 · Cited by 88
Banno, E., Togashi, Y., Nakamura, Y., Chiba, M., Kobayashi, Y., Hayashi, H., Terashima, M., de Velasco, M. A., Sakai, K., Fujita, Y., et al. (2016) · Cancer Science · doi:10.1111/cas.12980 · Cited by 87
Self-citationPilotto, S., Rossi, A., Vavalà, T., Follador, A., Tiseo, M., Galetta, D., Morabito, A., Di Maio, M., Martelli, O., Caffo, O., et al. (2018) · Clinical Lung Cancer · doi:10.1016/j.cllc.2017.05.016 · Cited by 46
Frega, S., Lorenzi, M., Fassan, M., Indraccolo, S., Calabrese, F., Favaretto, A., Bonanno, L., Polo, V., Zago, G., Lunardi, F., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.15945 · Cited by 17
Metadata
- Authors
- Kobayashi, Y., Togashi, Y., Yatabe, Y., Mizuuchi, H., Jangchul, P., Kondo, C., Shimoji, M., Sato, K., Suda, K., Tomizawa, K., Takemoto, T., Hida, T., Nishio, K., & Mitsudomi, T.
- Affiliations
- Kindai University (JP)
- Aichi Cancer Center (JP)
- Kitakyushu Municipal Medical Center (JP)
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2015-11-30
- Volume
- 21
- Issue
- 23
- Pages
- 5305-5313
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W1853526923
- Semantic Scholar
- 53af8bc0dfa0bc29df228e1b8265a22f4e341e60
- Cited by
- 203
- References
- 15
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 18 · 2023: 15 · 2022: 28 · 2021: 21 · 2020: 24 · 2019: 26 · 2018: 26 · 2017: 19 · 2016: 8 · 2015: 1
- FWCI
- 14.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (25293090, 26893310)
- 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
- lung cancer, EGFR tyrosine kinase inhibitors, afatinib, neratinib, gefitinib, erlotinib, osimertinib, exon 19 deletion, exon 20 insertion, L858R, drug sensitivity
- MeSH terms
- Afatinib, Animals, DNA Mutational Analysis, Exons, Gene Frequency, Humans, Lung Neoplasms, Male, Middle Aged, Models, Molecular, Molecular Conformation, Mutation, Quinazolines, Quinolines, Structure-Activity Relationship, Transfection, Gene Expression, Treatment Outcome, Drug Resistance, Neoplasm, Databases, Genetic, Cell Line, Tumor, Protein Kinase Inhibitors, Mice, Mutation Rate, ErbB Receptors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
