EGFR Fusions as Novel Therapeutic Targets in Lung Cancer

Konduri, Kartik; Gallant, Jean-Nicolas; Chae, Young Kwang; Giles, Francis J.; Gitlitz, Barbara J.; Gowen, Kyle; Ichihara, Eiki; Owonikoko, Taofeek K.; Peddareddigari, Vijay; Ramalingam, Suresh S.; Reddy, Satyanarayan K.; Eaby-Sandy, Beth; Vavalà, Tiziana; Whiteley, Andrew; Chen, Heidi; Yan, Yingjun; Sheehan, Jonathan H.; Meiler, Jens; Morosini, Deborah; Ross, Jeffrey S.; Stephens, Philip J.; Miller, Vincent A.; Ali, Siraj M.; Lovly, Christine M.

doi:10.1158/2159-8290.cd-16-0075

Cited by 144Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchCancer Genomics and Diagnostics

EGFR Fusions as Novel Therapeutic Targets in Lung Cancer

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Konduri, Kartik, Gallant, Jean-Nicolas, Chae, Young Kwang, Giles, Francis J., Gitlitz, Barbara J., Gowen, Kyle, Ichihara, Eiki, Owonikoko, Taofeek K. +16 more·2016·Cancer Discovery

DOI 10.1158/2159-8290.cd-16-0075PMC PMC4893907

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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.

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Exon 18 mutations include point mutations that in >80% of cases involve codons 719 or 709, and more rarely deletion-insertions.
“include point mutations, which, in >80% of cases, involve the codons 719 (G719X and the most common variants, G719A, G719S, and G719C) or 709 (E709X), and more rarely, deletion–insertions [19,29,30].”
From Heterogeneous Responses to Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs) in Patients with Uncommon EGFR Mutations: New Insights and Future Perspectives in this Complex Clinical Scenario (2019) · cites this paper as [29]
Exon 18 mutations collectively account for approximately 3-4% of all EGFR mutations.
“Exon 18 mutations collectively account for approximately 3–4% of all EGFR mutations”
From Heterogeneous Responses to Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs) in Patients with Uncommon EGFR Mutations: New Insights and Future Perspectives in this Complex Clinical Scenario (2019) · cites this paper as [29]

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P76.81 Primary Resistance to EGFR-TKIs in Lung Adenocarcinoma harboring EGFR–RAD51 Fusion: A Brief Report
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1360P Identification of epidermal growth factor receptor (EGFR) fusions in a large Chinese lung cancer population
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Authors: Konduri, K., Gallant, J.-N., Chae, Y. K., Giles, F. J., Gitlitz, B. J., Gowen, K., Ichihara, E., Owonikoko, T. K., Peddareddigari, V., Ramalingam, S. S., Reddy, S. K., Eaby-Sandy, B., Vavalà, T., Whiteley, A., Chen, H., Yan, Y., Sheehan, J. H., Meiler, J., Morosini, D., Ross, J. S., Stephens, P. J., Miller, V. A., Ali, S. M., & Lovly, C. M.
Affiliations: Baylor University Medical Center (US)
Vanderbilt University Medical Center (US)
Northwestern University (US)
University of Southern California (US)
Foundation Medicine (United States) (US)
Emory University (US)
Hospital of the University of Pennsylvania (US)
13Abramson Cancer Center, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.
Addario Lung Cancer Medical Institute (US)
Corresponding author: Lovly, Christine M.
ORCID: Gallant, Jean-Nicolas
Chae, Young Kwang
Giles, Francis J.
Gitlitz, Barbara J.
Ichihara, Eiki
Owonikoko, Taofeek K.
Ramalingam, Suresh S.
Vavalà, Tiziana
Chen, Heidi
Yan, Yingjun
Sheehan, Jonathan H.
Meiler, Jens
Ross, Jeffrey S.
Miller, Vincent A.
Ali, Siraj M.
Lovly, Christine M.
Venue: Cancer Discovery
Publisher: American Association for Cancer Research (AACR)
Published: 2016-06-01
Volume: 6
Issue: 6
Pages: 601-611
ISSN: 2159-8274 (ISSN-L)
2159-8290
DOI: 10.1158/2159-8290.cd-16-0075
PMC: PMC4893907
OpenAlex: W2337791749
Cited by: 144
References: 31
Citations by year: 2026: 5 · 2025: 8 · 2024: 18 · 2023: 14 · 2022: 13 · 2021: 28 · 2020: 13 · 2019: 14 · 2018: 12 · 2017: 11 · 2016: 7 · 2014: 1
FWCI: 13.12
Type: journal article
Language: en
Open access: green
europepmc.org
Locations: Cancer Discovery (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Heart, Lung, and Blood Institute (R01HL122010)
National Cancer Institute (R01CA121210, P01CA129243, F30CA206339, K12CA090625, P30CA060553)
National Institute of General Medical Sciences (R01GM073151, T32GM007347, R01GM099842, R01GM080403)
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK097376)
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords: lung cancer, EGFR tyrosine kinase inhibitors, erlotinib, therapeutic target, metastatic lung cancer, oncogenicity, therapeutic antibodies
MeSH terms: Adult, Antineoplastic Agents, Combined Modality Therapy, Exons, Female, Humans, Introns, Lung Neoplasms, Magnetic Resonance Imaging, Male, Middle Aged, Models, Molecular, Neoplasm Metastasis, Protein Conformation, Biomarkers, Oncogene Proteins, Fusion, Cell Line, Tumor, Protein Kinase Inhibitors, Rad51 Recombinase, Young Adult, Genetic Loci, Molecular Targeted Therapy, High-Throughput Nucleotide Sequencing, ErbB Receptors

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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EGFR Fusions as Novel Therapeutic Targets in Lung Cancer

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