Liquid biopsy monitoring uncovers acquired RAS-mediated resistance to cetuximab in a substantial proportion of patients with head and neck squamous cell carcinoma.
Oncotarget
; 7(28): 42988-42995, 2016 Jul 12.
Article
em En
| MEDLINE
| ID: mdl-27119512
ABSTRACT
Resistance to epidermal growth factor receptor (EGFR)-targeted therapy is insufficiently understood in head and neck squamous cell carcinoma (HNSCC), entailing the lack of predictive biomarkers.Here, we studied resistance-mediating EGFR ectodomain and activating RAS mutations by next-generation sequencing (NGS) of cell lines and tumor tissue of cetuximab-naïve patients (46 cases, 12 cell lines), as well as liquid biopsies taken during and after cetuximab/platinum/5-fluorouracil treatment (20 cases). Tumors of cetuximab-naïve patients were unmutated, except for HRAS mutations in 4.3% of patients. Liquid biopsies revealed acquired KRAS, NRAS or HRAS mutations in more than one third of patients after cetuximab exposure. 46% of patients with on-treatment disease progression showed acquired RAS mutations, while no RAS mutations were found in the non-progressive subset of patients, indicating that acquisition of RAS mutant clones correlated significantly with clinical resistance (Chi square p=0.032). The emergence of mutations preceded clinical progression in half of the patients, with a maximum time from mutation detection to clinical progression of 16 weeks.RAS mutations account for acquired resistance to EGFR-targeting in a substantial proportion of HNSCC patients, even though these tumors are rarely mutated at baseline. Liquid biopsies may be used for mutational monitoring to guide treatment decisions.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Carcinoma de Células Escamosas
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Proteínas ras
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Resistencia a Medicamentos Antineoplásicos
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Cetuximab
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Biópsia Líquida
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Neoplasias de Cabeça e Pescoço
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Oncotarget
Ano de publicação:
2016
Tipo de documento:
Article