EGFR Fusions as Novel Therapeutic Targets in Lung Cancer.

Abstract

UNLABELLED:

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.

SIGNIFICANCE:

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.

• Authors: Kartik Konduri, Jean-Nicolas Gallant, Young Kwang Chae, Francis J Giles, Barbara J Gitlitz, Kyle Gowen, Eiki Ichihara, Taofeek K Owonikoko, Vijay Peddareddigari, Suresh S Ramalingam, Satyanarayan K Reddy, Beth Eaby-Sandy, Tiziana Vavalà, Andrew Whiteley, Heidi Chen, Yingjun Yan, Jonathan H Sheehan, Jens Meiler, Deborah Morosini, Jeffrey S Ross, Philip J Stephens, Vincent A Miller, Siraj M Ali, Christine M Lovly
• Journal: Cancer discovery (Cancer Discov) Vol. 6 Issue 6 Pg. 601-11 (06 2016) ISSN: 2159-8290 [Electronic] United States
• PMID: 27102076 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Biomarkers
• Oncogene Proteins, Fusion
• Protein Kinase Inhibitors
• ErbB Receptors
• Rad51 Recombinase

Topics

• Adult
• Antineoplastic Agents (pharmacology, therapeutic use)
• Biomarkers
• Cell Line, Tumor
• Combined Modality Therapy
• ErbB Receptors (genetics)
• Exons
• Female
• Genetic Loci
• High-Throughput Nucleotide Sequencing
• Humans
• Introns
• Lung Neoplasms (diagnosis, drug therapy, genetics)
• Magnetic Resonance Imaging
• Male
• Middle Aged
• Models, Molecular
• Molecular Targeted Therapy
• Neoplasm Metastasis
• Oncogene Proteins, Fusion (antagonists & inhibitors, chemistry, genetics)
• Protein Conformation
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Rad51 Recombinase (genetics)
• Young Adult