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

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• dc.contributor.author Sánchez-Herrero, Estela
• dc.contributor.author Serna-Blasco, Roberto
• dc.contributor.author Ivanchuk, Vadym
• dc.contributor.author García-Campelo, Rosario
• dc.contributor.author Dómine Gómez, Manuel
• dc.contributor.author Sánchez, José M.
• dc.contributor.author Massutí, Bartomeu
• dc.contributor.author Reguart, Noemí
• dc.contributor.author Camps, Carlos
• dc.contributor.author Sanz-Moreno, Sandra
• dc.contributor.author Calabuig-Fariñas, Sílvia
• dc.contributor.author Jantus-Lewintre, Eloisa
• dc.contributor.author Arnal, Magdalena
• dc.contributor.author Fernández-Orth, Dietmar
• dc.contributor.author Calvo, Virginia
• dc.contributor.author González-Rumayor, Víctor
• dc.contributor.author Provencio, Mariano
• dc.contributor.author Romero, Atocha
• dc.date.accessioned 2021-10-22T06:00:19Z
• dc.date.available 2021-10-22T06:00:19Z
• dc.date.issued 2021
• dc.description.abstract 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.
• dc.description.sponsorship The authors wish to thank the donors, and the BIOBANK HOSPITAL UNIVERSITARIO PUERTA DE HIERRO MAJADAHONDA (HUPHM)/INSTITUTO DE INVESTIGACIÓN SANITARIA PUERTA DE HIERRO-SEGOVIA DE ARANA (IDIPHISA) (PT17/0015/0020 in the Spanish National Biobanks Network) for the human specimens used in this study. This study has been funded by Instituto de Salud Carlos III through the project ‘PI17/01977’ (Co-funded by European Regional Development Fund/European Social Fund ‘A way to make Europe’/‘Investing in your future’). The work presented in this paper also received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No 875160. ES was funded by the Consejería de Ciencia, Universidades e Innovación of the Comunidad de Madrid (Doctorados Industriales of the Comunidad de Madrid IND2019/BMD-17258). RS was funded by the Consejería de Educación, Juventud y Deporte of the Comunidad de Madrid and by the Fondo Social Europeo (Programa Operativo de Empleo Juvenil, and Iniciativa de Empleo Juvenil, PEJD-2018-PRE/BMD-8640).
• dc.format.mimetype application/pdf
• dc.identifier.citation 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. NGS-based liquid biopsy profiling identifies mechanisms of resistance to ALK inhibitors: a step toward personalized NSCLC treatment. Mol Oncol. 2021;15(9):2363-76. DOI: 10.1002/1878-0261.13033
• dc.identifier.doi http://dx.doi.org/10.1002/1878-0261.13033
• dc.identifier.issn 1574-7891
• dc.identifier.uri http://hdl.handle.net/10230/48755
• dc.language.iso eng
• dc.publisher Wiley
• dc.relation.ispartof Mol Oncol. 2021;15(9):2363-76
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/875160
• dc.rights © 2021 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword EML4-ALK
• dc.subject.keyword ALK-TKI
• dc.subject.keyword NGS
• dc.subject.keyword NSCLC
• dc.subject.keyword Liquid biopsy
• dc.title NGS-based liquid biopsy profiling identifies mechanisms of resistance to ALK inhibitors: a step toward personalized NSCLC treatment
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion