EGFR Kinase Domain Duplication (EGFR-KDD) Is a Novel Oncogenic Driver in Lung Cancer That Is Clinically Responsive to Afatinib.
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.


CONCLUSIONS
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.
Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee. Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
Jean-Nicolas
JN
Gallant
Department of Biochemistry, Vanderbilt University Medical Center, Nashville, Tennessee. Center for Structural Biology, Vanderbilt University Medical Center, Nashville, Tennessee.
Jonathan H
JH
Sheehan
Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee. Department of Biochemistry, Vanderbilt University Medical Center, Nashville, Tennessee.
Timothy M
TM
Shaver
Foundation Medicine Inc., Cambridge, Massachusetts.
Mark
M
Bailey
Foundation Medicine Inc., Cambridge, Massachusetts.
Doron
D
Lipson
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
Raghu
R
Chandramohan
Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
Monica
M
Red Brewer
Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
Sally J
SJ
York
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Mark G
MG
Kris
Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee. Department of Biochemistry, Vanderbilt University Medical Center, Nashville, Tennessee.
Jennifer A
JA
Pietenpol
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
Marc
M
Ladanyi
Foundation Medicine Inc., Cambridge, Massachusetts.
Vincent A
VA
Miller
Foundation Medicine Inc., Cambridge, Massachusetts.
Siraj M
SM
Ali
Center for Structural Biology, Vanderbilt University Medical Center, Nashville, Tennessee. Department of Chemistry, Vanderbilt University Medical Center, Nashville, Tennessee.
Jens
J
Meiler
Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee. Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. christine.lovly@vanderbilt.edu.
Christine M
CM
Lovly
D000328:Adult; D000077716:Afatinib; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics*; D020440:Gene Duplication; D005787:Gene Frequency; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D009154:Mutation; D009367:Neoplasm Staging; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D055503:Protein Multimerization; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077716:Afatinib; D066246:ErbB Receptors