2015
DOI: 10.1038/nm.3854
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Acquired EGFR C797S mutation mediates resistance to AZD9291 in non–small cell lung cancer harboring EGFR T790M

Abstract: Here we studied cell-free plasma DNA (cfDNA) collected from subjects with advanced lung cancer whose tumors had developed resistance to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) AZD9291. We first performed next-generation sequencing of cfDNA from seven subjects and detected an acquired EGFR C797S mutation in one; expression of this mutant EGFR construct in a cell line rendered it resistant to AZD9291. We then performed droplet digital PCR on serial cfDNA specimens collected fr… Show more

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Cited by 1,316 publications
(1,176 citation statements)
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“…There were several patterns of progression identified; some patients had reemergence of both the activating EGFR mutation and T790M cfDNA; some patients had continued suppression of both mutations despite clinical progression, while others had emergence of either EGFR T790M or activating EGFR mutation cfDNA. A few patients acquired an EGFR C797S mutation in plasma, which has previously been reported as a resistance mechanism in patients treated with osimertinib (19,21). Various limitations, however, exist that must be addressed to further refine the use of these approaches in both clinical research and clinical practice.…”
Section: Discussionmentioning
confidence: 80%
See 1 more Smart Citation
“…There were several patterns of progression identified; some patients had reemergence of both the activating EGFR mutation and T790M cfDNA; some patients had continued suppression of both mutations despite clinical progression, while others had emergence of either EGFR T790M or activating EGFR mutation cfDNA. A few patients acquired an EGFR C797S mutation in plasma, which has previously been reported as a resistance mechanism in patients treated with osimertinib (19,21). Various limitations, however, exist that must be addressed to further refine the use of these approaches in both clinical research and clinical practice.…”
Section: Discussionmentioning
confidence: 80%
“…Failure to clear cfDNA-harboring EGFR mutations predicts shorter response and inferior outcomes with EGFR TKI treatment (15,18). Similarly, a decline in the activating mutations and EGFR T790M occurs when treated with a thirdgeneration EGFR TKI and can begin to rise again with the emergence of resistance (19).…”
Section: Introductionmentioning
confidence: 99%
“…Since acquired resistance uniformly develops with the use of third-generation EGFR inhibitors as well, case reports and case series are emerging identifying analogous mechanisms of secondary acquired resistance with novel EGFR mutations (C797S) that disallow covalent binding of thirdgeneration EGFR inhibitors as well as bypass resistance via MET pathway activation (36).…”
Section: Met In Resistance To Third-generation Egfr Tkismentioning
confidence: 99%
“…Additionally, the FLAURA trial (NCT02296125), an ongoing phase III trial to confirm the superiority of first-line osimertinib to first-generation EGFR-TKI will change the current treatment. Following an acquired resistance for osimertinib, C797S (23), and the targeted agent EAI045.3 (24) should be administered. Therefore, oncologists must confirm the optimal sequential strategy with or without other cytotoxic and molecular targeted agents.…”
mentioning
confidence: 99%