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 10-35% 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 (TKIs). 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, re-sequencing revealed an EGFR-dependent mechanism of acquired resistance to afatinib, thereby validating EGFR-KDD as a driver alteration and therapeutic target.

Kinase inhibitor-responsive genotypes in EGFR mutated lung adenocarcinomas: moving past common point mutations or indels into uncommon kinase domain duplications and rearrangements

“…This type of EGFR-KDD had only been previously reported in rare cases of glioma (36) and was additionally found to occur in sarcomas, peritoneal carcinomas and Wilms' tumors (34). In preclinical and computational models, the resulting EGFR-KDD protein is transforming, may generate EGFR intramolecular asymmetric activated dimers, and is hypersensitive to 1 st , 2 nd and 3 rd generation EGFR TKIs (34). The same report also describes a case of advanced chemotherapyprogressive EGFR-KDD mutated lung adenocarcinoma with a 7-month partial response to afatinib (doses not provided) and subsequent progression due to amplification of the EGFR-KDD allele (34).…”

“…As these exons encompass the tyrosine kinase domain, this duplication generates an in-frame kinase domain duplication at the protein level. This type of EGFR-KDD had only been previously reported in rare cases of glioma (36) and was additionally found to occur in sarcomas, peritoneal carcinomas and Wilms' tumors (34). In preclinical and computational models, the resulting EGFR-KDD protein is transforming, may generate EGFR intramolecular asymmetric activated dimers, and is hypersensitive to 1 st , 2 nd and 3 rd generation EGFR TKIs (34).…”

“…Eloquent structural and biochemical experiments have irrefutably defined that the addition of EGFR-T790M to a sensitizing mutant alters the kinetics of inhibitor binding of gefitinib, erlotinib and afatinib (29,30); leading to resistance to achievable clinical doses of these EGFR TKIs. However, 3 rd generation EGFR TKIs that were selected on the basis of their covalent binding to EGFR-C797, plus their mutation over WT EGFR sensitivity, can inhibit EGFR-T790M bearing cancers (6,31 and EGFR rearrangements (34,35). It seems the frequency of these changes does not exceed individually 0.5% of all EGFR mutation events ( Table 1).…”

“…The EGFR-KDD alteration consists of an intragenic alteration in EGFR, resulting in the tandem duplication of exons 18 to 25 (34). As these exons encompass the tyrosine kinase domain, this duplication generates an in-frame kinase domain duplication at the protein level.…”

“…In preclinical and computational models, the resulting EGFR-KDD protein is transforming, may generate EGFR intramolecular asymmetric activated dimers, and is hypersensitive to 1 st , 2 nd and 3 rd generation EGFR TKIs (34). The same report also describes a case of advanced chemotherapyprogressive EGFR-KDD mutated lung adenocarcinoma with a 7-month partial response to afatinib (doses not provided) and subsequent progression due to amplification of the EGFR-KDD allele (34). Another case report of a prolonged multi-year response to gefitinib and then erlotinib has been described for advanced EGFR-KDD mutated lung adenocarcinoma (37).…”