Molecular Divergence upon EGFR -TKI Resistance Could Be Dependent on the Exon Location of the Original EGFR -Sensitizing Mutation

• Published in: Cancers 2022-09, Vol.14 (18), p.4446
• Main Authors: Serna-Blasco, Roberto, Sánchez-Herrero, Estela, Robado de Lope, Lucía, Sanz-Moreno, Sandra, Rodríguez-Festa, Alejandro, Ares-Trotta, Dunixe, Cruz-Bermúdez, Alberto, Franco, Fabio, Sánchez-Hernández, Alfredo, Campayo, María de Julián, García-Girón, Carlos, Dómine, Manuel, Blasco, Ana, Sánchez, José M, Oramas, Juana, Bosch-Barrera, Joaquim, Sala, María Á, Sereno, María, Romero, Atocha, Provencio, Mariano
• Format: Article
• Language: English
• Subjects: Adenomatous polyposis coli; Biopsy; Cancer therapies; Disease resistance; Divergence; Enzyme inhibitors; Epidermal growth factor receptors; Exons; Fibroblast growth factor receptors; Gene deletion; Lung cancer; Medical prognosis; Mutation; Next-generation sequencing; Non-small cell lung carcinoma; Nucleotide sequence; p53 Protein; Protein-tyrosine kinase; Tumors
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers14184446

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.