EGFR Fusions as Novel Therapeutic Targets in Lung Cancer.
Here, we report that novel epidermal growth factor receptor (EGFR) gene fusions comprising the N-terminal of EGFR linked to various fusion partners, most commonly RAD51, are recurrent in lung cancer. We describe five patients with metastatic lung cancer whose tumors harbored EGFR fusions, four of whom were treated with EGFR tyrosine kinase inhibitors (TKI) with documented antitumor responses. In vitro, EGFR-RAD51 fusions are oncogenic and can be therapeutically targeted with available EGFR TKIs and therapeutic antibodies. These results support the dependence of EGFR-rearranged tumors on EGFR-mediated signaling and suggest several therapeutic strategies for patients whose tumors harbor this novel alteration.



We report for the first time the identification and therapeutic targeting of EGFR C-terminal fusions in patients with lung cancer and document responses to the EGFR inhibitor erlotinib in 4 patients whose tumors harbored EGFR fusions. Findings from these studies will be immediately translatable to the clinic, as there are already several approved EGFR inhibitors. Cancer Discov; 6(6); 601-11. ©2016 AACR.See related commentary by Paik, p. 574This article is highlighted in the In This Issue feature, p. 561.
Baylor University Medical Center, Baylor Sammons Cancer Center, Dallas, Texas. Texas Oncology PA, Dallas, Texas.
Kartik
K
Konduri
Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee.
Jean-Nicolas
JN
Gallant
Northwestern Medicine Developmental Therapeutics Institute, Chicago, Illinois. Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois. Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Young Kwang
YK
Chae
Northwestern Medicine Developmental Therapeutics Institute, Chicago, Illinois. Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois. Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Francis J
FJ
Giles
Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, California. Addario Lung Cancer Medical Institute, Cambridge, Massachusetts.
Barbara J
BJ
Gitlitz
Foundation Medicine, Inc., Cambridge, Massachusetts.
Kyle
K
Gowen
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
Eiki
E
Ichihara
Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia. Winship Cancer Institute, Atlanta, Georgia.
Taofeek K
TK
Owonikoko
Abramson Cancer Center, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania. Janssen Research & Development, LLC, Horsham, Pennsylvania.
Vijay
V
Peddareddigari
Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia. Winship Cancer Institute, Atlanta, Georgia.
Suresh S
SS
Ramalingam
Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia. Winship Cancer Institute, Atlanta, Georgia.
Satyanarayan K
SK
Reddy
Abramson Cancer Center, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.
Beth
B
Eaby-Sandy
Addario Lung Cancer Medical Institute, Cambridge, Massachusetts. Department of Oncology, Thoracic Oncology Unit, University of Turin, Italy.
Tiziana
T
Vavalà
Baylor University Medical Center, Baylor Sammons Cancer Center, Dallas, Texas.
Andrew
A
Whiteley
Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee.
Heidi
H
Chen
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
Yingjun
Y
Yan
Department of Biochemistry, Vanderbilt University Medical Center, Nashville, Tennessee. Center for Structural Biology, Vanderbilt University Medical Center, Nashville, Tennessee.
Jonathan H
JH
Sheehan
Center for Structural Biology, Vanderbilt University Medical Center, Nashville, Tennessee. Department of Chemistry, Vanderbilt University Medical Center, Nashville, Tennessee.
Jens
J
Meiler
Foundation Medicine, Inc., Cambridge, Massachusetts.
Deborah
D
Morosini
Foundation Medicine, Inc., Cambridge, Massachusetts. Albany Medical College, Albany, New York.
Jeffrey S
JS
Ross
Foundation Medicine, Inc., Cambridge, Massachusetts.
Philip J
PJ
Stephens
Foundation Medicine, Inc., Cambridge, Massachusetts.
Vincent A
VA
Miller
Foundation Medicine, Inc., Cambridge, Massachusetts.
Siraj M
SM
Ali
Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee. Addario Lung Cancer Medical Institute, Cambridge, Massachusetts. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee. christine.lovly@vanderbilt.edu.
Christine M
CM
Lovly
D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D066246:ErbB Receptors / Q000235:genetics*; D005091:Exons; D005260:Female; D056426:Genetic Loci; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007438:Introns; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics*; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D051135:Rad51 Recombinase / Q000235:genetics; D055815:Young Adult
D000970:Antineoplastic Agents; D015415:Biomarkers; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors; D051135:Rad51 Recombinase