Acquired BRAF rearrangements induce secondary resistance to EGFR therapy in EGFR-mutated lung cancers Journal Article

Authors: Vojnic, M.; Kubota, D.; Kurzatkowski, C.; Offin, M.; Suzawa, K.; Benayed, R.; Schoenfeld, A. J.; Plodkowski, A. J.; Poirier, J. T.; Rudin, C. M.; Kris, M. G.; Rosen, N. X.; Yu, H. A.; Riely, G. J.; Arcila, M. E.; Somwar, R.; Ladanyi, M.
Article Title: Acquired BRAF rearrangements induce secondary resistance to EGFR therapy in EGFR-mutated lung cancers
Abstract: Introduction: Multiple genetic mechanisms have been identified in EGFR-mutant lung cancers as mediators of acquired resistance (AR) to EGFR tyrosine kinase inhibitors (TKIs), but many cases still lack a known mechanism. Methods: To identify novel mechanisms of AR, we performed targeted large panel sequencing of samples from 374 consecutive patients with metastatic EGFR-mutant lung cancer, including 174 post-TKI samples, of which 38 also had a matched pre-TKI sample. Alterations hypothesized to confer AR were introduced into drug-sensitive EGFR-mutant lung cancer cell lines (H1975, HCC827, and PC9) by using clustered regularly interspaced short palindromic repeats/Cas9 genome editing. MSK-LX138cl, a cell line with EGFR exon 19 deletion (ex19del) and praja ring finger ubiquitin ligase 2 gene (PJA2)/BRAF fusion, was generated from an EGFR TKI–resistant patient sample. Results: We identified four patients (2.3%) with a BRAF fusion (three with acylglycerol kinase gene (AGK)/BRAF and one with PJA2/BRAF) in samples obtained at AR to EGFR TKI therapy (two posterlotinib samples and two posterlotinib and postosimertinib samples). Pre-TKI samples were available for two of four patients and both were negative for BRAF fusion. Induction of AGK/BRAF fusion in H1975 (L858R + T790M), PC9 (ex19del) and HCC827 (ex19del) cells increased phosphorylation of BRAF, MEK1/2, ERK1/2, and signal transducer and activator of transcription 3 and conferred resistance to growth inhibition by osimertinib. MEK inhibition with trametinib synergized with osimertinib to block growth. Alternately, a pan-RAF inhibitor as a single agent blocked growth of all cell lines with mutant EGFR and BRAF fusion. Conclusion: BRAF fusion is a mechanism of AR to EGFR TKI therapy in approximately 2% of patients. Combined inhibition of EGFR and MEK (with osimertinib and trametinib) or BRAF (with a pan-RAF inhibitor) are potential therapeutic strategies that should be explored. © 2019 International Association for the Study of Lung Cancer
Keywords: lung adenocarcinoma; egfr; acquired resistance; crispr-cas9; osimertinib; braf fusion
Journal Title: Journal of Thoracic Oncology
Volume: 14
Issue: 5
ISSN: 1556-0864
Publisher: Elsevier Inc.  
Date Published: 2019-05-01
Start Page: 802
End Page: 815
Language: English
DOI: 10.1016/j.jtho.2018.12.038
PROVIDER: scopus
PMCID: PMC6486868
PUBMED: 30831205
Notes: Article -- Export Date: 1 May 2019 -- Source: Scopus
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MSK Authors
  1. Neal Rosen
    372 Rosen
  2. Helena Alexandra Yu
    104 Yu
  3. Marc Ladanyi
    943 Ladanyi
  4. Gregory J Riely
    378 Riely
  5. Romel Somwar
    41 Somwar
  6. Maria Eugenia Arcila
    396 Arcila
  7. Mark Kris
    667 Kris
  8. Charles Rudin
    183 Rudin
  9. Rym Benayed
    89 Benayed
  10. John Thomas Poirier
    62 Poirier
  11. Michael David Offin
    28 Offin
  12. Ken Suzawa
    7 Suzawa
  13. Morana Vojnic
    4 Vojnic
  14. Daisuke Kubota
    1 Kubota