Genomic and biological study of fusion genes as resistance mechanisms to EGFR inhibitors

Yoshihisa Kobayashi, Geoffrey R. Oxnard, Elizabeth F. Cohen, Navin R. Mahadevan, Joao V. Alessi, Yin P. Hung, Arrien A. Bertram, David E. Heppner, Mauricio F. Ribeiro, Karina P. Sacardo, Rodrigo Saddi, Mariana P. Macedo, Rafael B. Blasco, Jiaqi Li, Kari J. Kurppa, Tom Nguyen, Emma Voligny, Guruprasad Ananda, Roberto Chiarle, Artur Katz, Michael Y. Tolstorukov, Lynette M. Sholl and Pasi A. Jänne ()
Additional contact information
Yoshihisa Kobayashi: Dana-Farber Cancer Institute and Harvard Medical School
Geoffrey R. Oxnard: Dana-Farber Cancer Institute
Elizabeth F. Cohen: Dana-Farber Cancer Institute
Navin R. Mahadevan: Dana-Farber Cancer Institute and Harvard Medical School
Joao V. Alessi: Dana-Farber Cancer Institute
Yin P. Hung: Massachusetts General Hospital
Arrien A. Bertram: Dana-Farber Cancer Institute
David E. Heppner: University at Buffalo, State University of New York
Mauricio F. Ribeiro: Hospital Sírio-Libanês
Karina P. Sacardo: Hospital Sírio-Libanês
Rodrigo Saddi: Hospital Sírio-Libanês
Mariana P. Macedo: Hospital Sírio-Libanês
Rafael B. Blasco: Boston Children’s Hospital
Jiaqi Li: Dana-Farber Cancer Institute and Harvard Medical School
Kari J. Kurppa: University of Turku
Tom Nguyen: Dana-Farber Cancer Institute
Emma Voligny: Dana-Farber Cancer Institute
Guruprasad Ananda: Dana-Farber Cancer Institute
Roberto Chiarle: Boston Children’s Hospital
Artur Katz: Hospital Sírio-Libanês
Michael Y. Tolstorukov: Dana-Farber Cancer Institute
Lynette M. Sholl: Brigham and Women’s Hospital
Pasi A. Jänne: Dana-Farber Cancer Institute and Harvard Medical School

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract The clinical significance of gene fusions detected by DNA-based next generation sequencing remains unclear as resistance mechanisms to EGFR tyrosine kinase inhibitors in EGFR mutant non-small cell lung cancer. By studying EGFR inhibitor-resistant patients treated with a combination of an EGFR inhibitor and a drug targeting the putative resistance-causing fusion oncogene, we identify patients who benefit and those who do not from this treatment approach. Through evaluation including RNA-seq of potential drug resistance-imparting fusion oncogenes in 504 patients with EGFR mutant lung cancer, we identify only a minority of them as functional, potentially capable of imparting EGFR inhibitor resistance. We further functionally validate fusion oncogenes in vitro using CRISPR-based editing of EGFR mutant cell lines and use these models to identify known and unknown drug resistance mechanisms to combination therapies. Collectively, our results partially reveal the complex nature of fusion oncogenes as potential drug resistance mechanisms and highlight approaches that can be undertaken to determine their functional significance.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33210-2

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DOI: 10.1038/s41467-022-33210-2

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