학술논문
Molecular Divergence upon EGFR-TKI Resistance Could Be Dependent on the Exon Location of the Original EGFR-Sensitizing Mutation
Document Type
article
Author
Roberto Serna-Blasco; Estela Sánchez-Herrero; Lucía Robado de Lope; Sandra Sanz-Moreno; Alejandro Rodríguez-Festa; Dunixe Ares-Trotta; Alberto Cruz-Bermúdez; Fabio Franco; Alfredo Sánchez-Hernández; María de Julián Campayo; Carlos García-Girón; Manuel Dómine; Ana Blasco; José M. Sánchez; Juana Oramas; Joaquim Bosch-Barrera; María Á. Sala; María Sereno; Atocha Romero; Mariano Provencio
Source
Cancers, Vol 14, Iss 18, p 4446 (2022)
Subject
Language
English
ISSN
2072-6694
Abstract
Tumor molecular profiling upon disease progression enables investigations of the tumor evolution. Next-generation sequencing (NGS) of liquid biopsies constitutes a noninvasive readily available source of tumor molecular information. In this study, 124 plasma samples from advanced EGFR-positive NSCLC patients, treated with a first-line EGFR tyrosine kinase inhibitor (EGFR-TKI) were collected upon disease progression. The circulating cell-free DNA (cfDNA) was sequenced using the Oncomine Pan-Cancer Cell-Free Assay™. Excluding EGFR mutations, the most frequently mutated gene was TP53 (57.3%), followed by APC (11.3%), FGFR3 (7.3%), and KRAS (5.6%). Different molecular alterations were observed upon disease progression depending on the location of the original EGFR-sensitizing mutation. Specifically, the detection of the p.T790M mutation was significantly associated with the presence of exon 19 mutations in EGFR (Fisher p-value: 0.028). All KRAS activating mutations (n = 8) were detected in tumors with EGFR mutations in exons 18 and 21 (Fisher p-value < 0.001). Similarly, mutations in NRAS and HRAS were more frequently detected in samples from tumors harboring mutations in exons 18 or 21 (Fisher p-value: 0.050 and Fisher p-value: 0.099, respectively). In conclusion, our data suggest that the mechanisms underlying EGFR-TKI resistance could be dependent on the exon location of the original EGFR-sensitizing mutation.