EGFR kinase domain duplication (EGFR -KDD) is a novel oncogenic driver in lung cancer that is clinically responsive to afatinib Journal Article

   

Authors:	Gallant, J. N.; Sheehan, J. H.; Shaver, T. M.; Bailey, M.; Lipson, D.; Chandramohan, R.; Brewer, M. R.; York, S. J.; Kris, M. G.; Pietenpol, J. A.; Ladanyi, M.; Miller, V. A.; Ali, S. M.; Meiler, J.; Lovly, C. M.
Article Title:	EGFR kinase domain duplication (EGFR -KDD) is a novel oncogenic driver in lung cancer that is clinically responsive to afatinib
Abstract:	Oncogenic EGFR mutations are found in 10% to 35% of lung adenocarcinomas. Such mutations, which present most commonly as small in-frame deletions in exon 19 or point mutations in exon 21 (L858R), confer sensitivity to EGFR tyrosine kinase inhibitors (TKI). In analyzing the tumor from a 33-year-old male never-smoker, we identified a novel EGFR alteration in lung cancer: EGFR exon 18–25 kinase domain duplication (EGFR -KDD). Through analysis of a larger cohort of tumor samples, we detected additional cases of EGFR- KDD in lung, brain, and other cancers. In vitro, EGFR-KDD is constitutively active, and computational modeling provides potential mechanistic support for its auto-activation. EGFR -KDD–transformed cells are sensitive to EGFR TKIs and, consistent with these in vitro findings, the index patient had a partial response to the EGFR TKI afatinib. The patient eventually progressed, at which time resequencing revealed an EGFR-dependent mechanism of acquired resistance to afatinib, thereby validating EGFR -KDD as a driver alteration and therapeutic target. SIGNIFICANCE: We identified oncogenic and drug-sensitive EGFR -KDD that is recurrent in lung, brain, and soft-tissue cancers and documented that a patient with metastatic lung adenocarcinoma harboring the EGFR- KDD derived significant antitumor response from treatment with the EGFR inhibitor afatinib. Findings from these studies will be immediately translatable, as there are already several approved EGFR inhibitors in clinical use. © 2015 American Association for Cancer Research.
Keywords:	adult; cancer chemotherapy; controlled study; human tissue; treatment response; gene mutation; human cell; fatigue; case report; bevacizumab; cisplatin; erlotinib; nonhuman; animal cell; cell viability; computer assisted tomography; multiple cycle treatment; epidermal growth factor receptor; lung cancer; tumor biopsy; in vitro study; autophosphorylation; cancer resistance; coughing; lung adenocarcinoma; fluorescence in situ hybridization; glioblastoma; western blotting; gene duplication; protein structure; clonogenic assay; transient transfection; pemetrexed; genetic transformation; agar; afatinib; human; male; article; cell counting; lung cancer cell line; osimertinib
Journal Title:	Cancer Discovery
Volume:	5
Issue:	11
ISSN:	2159-8274
Publisher:	American Association for Cancer Research
Date Published:	2015-11-01
Start Page:	1155
End Page:	1163
Language:	English
DOI:	10.1158/2159-8290.cd-15-0654
PROVIDER:	scopus
PMCID:	PMC4631701
PUBMED:	26286086
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84946212527&partnerID=40&md5=91e6cd91b17891c0fbf949499b0d5641
Notes:	Export Date: 2 December 2015 -- Source: Scopus

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