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Characterization of acquired receptor tyrosine–kinase fusions as mechanisms of resistance to EGFR tyrosine–kinase inhibitors

Authors Xu H, Shen J, Xiang J, Li H, Li B, Zhang T, Zhang L, Mao X, Jian H, Shu Y

Received 6 December 2018

Accepted for publication 15 April 2019

Published 9 July 2019 Volume 2019:11 Pages 6343—6351

DOI https://doi.org/10.2147/CMAR.S197337

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Ms Justinn Cochran

Peer reviewer comments 2

Editor who approved publication: Dr Kenan Onel


Haiyuan Xu,1,2,* Jinge Shen,3,* Jianxing Xiang,4 Haiyan Li,4 Bing Li,4 Tengfei Zhang,4 Lu Zhang,4 Xinru Mao,4 Hong Jian,5 Yongqian Shu1

1Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, People’s Republic of China; 2Department of Oncology, Kunshan First People‘s Hospital affiliated to Jiangsu University, Kunshan 215300, People’s Republic of China; 3Department of Emergency, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai 200000, People’s Republic of China; 4Burning Rock Biotech, Guangzhou 510000, People’s Republic of China; 5Department of Oncology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai 200000, People’s Republic of China

*These authors contributed equally to this work

Purpose: Responses to EGFR-targeted therapy are generally temporary, due to inevitable drug resistance. The prevalence and characteristics of receptortyrosine–kinase (RTK) fusion as acquired resistance to EGFR tyrosine–kinase inhibitors (TKIs) are rarely investigated.
Methods: We retrospectively reviewed genomic profiling data of 3873 EGFR (exons 18–21)-mutant lung cancer patients with more than once next-generation sequencing detection. A total of 16 patients who acquired RTK fusions during EGFR-TKI treatment with paired pre- and post-EGFR-TKI samples were identified. Their treatment history was collected.
Results: Newly acquired RTK fusions during EGFR-TKI treatment included RET (n=6, 37.5%), ALK (n=5, 31.3%), NTRK1 (n=4, 25.0%), ROS1 (n=1, 6.3%), and FGFR3 (n=1, 6.3%). All RET and EML4ALK fusions were uncommon variants of KIF5B-RET and E2:A20 (V5), respectively. Interestingly, RET fusion occurred only after osimertinib treatment, and contributed to drug resistance in 50% (6 of 12) of patients treated with osimertinib, indicating that fusions had different prevalence when functioning as resistance mechanisms to EGFR TKIs. Moreover, we found that in all patients developing drug resistance to EGFR TKIs due to fusion emergence (n=16), those that had a treatment history of third-generation EGFR TKIs accounted for 75% (n=12).
Conclusion: We have extended the current knowledge of resistance mechanisms to EGFR TKIs in non-small-celllung cancer. Detection of RTK fusions should be included in genomic profiling panels to uncover potential resistance mechanisms of EGFR TKIs, which might inform therapeutic strategies, such as combination-therapy approaches, to circumvent tumorigenesis.

Keywords: receptor tyrosine kinase fusions, acquired resistance, EGFR tyrosine kinase inhibitors, lung cancer

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