NGS-based liquid biopsy profiling identifies mechanisms of resistance to ALK inhibitors: a step toward personalized NSCLC treatment

Autor: Sánchez-Herrero E, Serna-Blasco R, Ivanchuk V, García-Campelo R, Dómine Gómez M, Sánchez JM, Massutí B, Reguart N, Camps C, Sanz-Moreno S, Calabuig-Fariñas S, Jantus-Lewintre E, Arnal M, Fernández-Orth D, Calvo V, González-Rumayor V, Provencio M, Romero A
Rok vydání: 2021
Předmět:
Zdroj: MOLECULAR ONCOLOGY
r-ISABIAL. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica y Sanitaria de Alicante
instname
Molecular Oncology
r-FIHGUV. Repositorio Institucional de Producción Científica de la Fundación de Investigación del Hospital General de Valencia
ISSN: 1574-7891
Popis: Despite impressive and durable responses, nonsmall cell lung cancer (NSCLC) patients treated with anaplastic lymphoma kinase (ALK) inhibitors (ALK-Is) ultimately progress due to development of resistance. Here, we have evaluated the clinical utility of circulating tumor DNA (ctDNA) profiling by next-generation sequencing (NGS) upon disease progression. We collected 26 plasma and two cerebrospinal fluid samples from 24 advanced ALK-positive NSCLC patients at disease progression to an ALK-I. These samples were analyzed by NGS and digital PCR. A tool to retrieve variants at the ALK locus was developed (VALK tool). We identified at least one resistance mutation in the ALK locus in ten (38.5%) plasma samples; the G1269A and G1202R mutations were the most prevalent among patients progressing to first- and second-generation ALK-Is, respectively. Overall, 61 somatic mutations were detected in 14 genes: TP53, ALK, PIK3CA, SMAD4, MAP2K1 (MEK1), FGFR2, FGFR3, BRAF, EGFR, IDH2, MYC, MET, CCND3, and CCND1. Specifically, a deletion in exon 19 in EGFR, a non-V600 BRAF mutation (G466V), and the F129L mutation in MAP2K1 were identified in four patients who showed no objective survival benefit from ALK-Is. Potential ALK-I-resistance mutations were also found in PIK3CA and IDH2. Finally, a c-MYC gain, along with a loss of CCND1 and FGFR3, was detected in a patient progressing on a first-line treatment with crizotinib. We conclude that NGS analysis of liquid biopsies upon disease progression identified different putative ALK-I-resistance mutations in most cases and could be a valuable approach for therapy decision making.
Databáze: OpenAIRE
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