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Genomic and biological study of fusion genes as resistance mechanisms to EGFR inhibitors.
Kobayashi, Yoshihisa; Oxnard, Geoffrey R; Cohen, Elizabeth F; Mahadevan, Navin R; Alessi, Joao V; Hung, Yin P; Bertram, Arrien A; Heppner, David E; Ribeiro, Mauricio F; Sacardo, Karina P; Saddi, Rodrigo; Macedo, Mariana P; Blasco, Rafael B; Li, Jiaqi; Kurppa, Kari J; Nguyen, Tom; Voligny, Emma; Ananda, Guruprasad; Chiarle, Roberto; Katz, Artur; Tolstorukov, Michael Y; Sholl, Lynette M; Jänne, Pasi A.
Afiliação
  • Kobayashi Y; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, 02215, USA.
  • Oxnard GR; Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, 1040045, Japan.
  • Cohen EF; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
  • Mahadevan NR; Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
  • Alessi JV; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, 02215, USA.
  • Hung YP; Department of Pathology, Brigham and Women's Hospital, Boston, MA, 02115, USA.
  • Bertram AA; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
  • Heppner DE; Department of Pathology, Massachusetts General Hospital, Boston, MA, 02114, USA.
  • Ribeiro MF; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
  • Sacardo KP; Department of Chemistry, University at Buffalo, State University of New York, Buffalo, NY, 14260-3000, USA.
  • Saddi R; Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA.
  • Macedo MP; Department of Medical Oncology, Hospital Sírio-Libanês, São Paulo-SP, 01308-050, Brazil.
  • Blasco RB; Department of Medical Oncology, Hospital Sírio-Libanês, São Paulo-SP, 01308-050, Brazil.
  • Li J; Department of Medical Oncology, Hospital Sírio-Libanês, São Paulo-SP, 01308-050, Brazil.
  • Kurppa KJ; Department of Pathology, Hospital Sírio-Libanês, São Paulo-SP, 01308-050, Brazil.
  • Nguyen T; Department of Pathology, Boston Children's Hospital, Boston, MA, 02115, USA.
  • Voligny E; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, 02215, USA.
  • Ananda G; Institute of Biomedicine, and MediCity Research Laboratories, University of Turku, Turku, 20520, Finland.
  • Chiarle R; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
  • Katz A; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
  • Tolstorukov MY; Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
  • Sholl LM; Department of Pathology, Boston Children's Hospital, Boston, MA, 02115, USA.
  • Jänne PA; Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, 10126, Italy.
Nat Commun ; 13(1): 5614, 2022 09 24.
Article em En | MEDLINE | ID: mdl-36153311
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Carcinoma Pulmonar de Células não Pequenas / Receptores ErbB / Neoplasias Pulmonares Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Carcinoma Pulmonar de Células não Pequenas / Receptores ErbB / Neoplasias Pulmonares Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article