Identification of osimertinib-resistant EGFR L792 mutations by cfDNA sequencing: oncogenic activity assessment and prevalence in large cfDNA cohort
Posted on 2019-10-11 - 05:39
Abstract Cell-free DNA (cfDNA) next-generation sequencing has the potential to capture tumor heterogeneity and genomic evolution under treatment pressure in a non-invasive manner. Here, we report the detection of EGFR L792 mutations, a non-covalent mechanism of osimertinib resistance, using Guardant360 cfDNA testing in a patient with metastatic EGFR-mutant non-small cell lung cancer (NSCLC) whose disease progressed on osimertinib. We subsequently analyzed a large cohort of over 1800 additional patient samples harboring an EGFR T790M mutation and identified a concomitant L792 mutation in a total of 22 (1.2%) cases. In vitro functional assays demonstrated that the EGFR L858R/T790M/L792F/H mutations conferred intermediate-level resistance to osimertinib. Further understanding of potential acquired resistance mechanisms to targeted therapy may help inform treatment strategy in EGFR-mutant NSCLC.
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Fairclough, Stephen; Kiedrowski, Lesli; Lin, Jessica; Zelichov, Ori; Tarcic, Gabi; Stinchcombe, Thomas; et al. (2019). Identification of osimertinib-resistant EGFR L792 mutations by cfDNA sequencing: oncogenic activity assessment and prevalence in large cfDNA cohort. figshare. Collection. https://doi.org/10.6084/m9.figshare.c.4694918.v1
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AUTHORS (10)
SF
Stephen Fairclough
LK
Lesli Kiedrowski
JL
Jessica Lin
OZ
Ori Zelichov
GT
Gabi Tarcic
TS
Thomas Stinchcombe
JO
Justin Odegaard
RL
Richard Lanman
AS
Alice Shaw
RN
Rebecca Nagy