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 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 May 2019 -- Source: Scopus |
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