期刊
ONCOTARGET
卷 7, 期 28, 页码 42988-42995出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.8943
关键词
head and neck squamous cell carcinoma (HNSCC); epidermal growth factor receptor (EGFR); RAS; resistance; cetuximab
资金
- Deutsche Forschungsgemeinschaft [BI 1711/1-1]
- Hubertus Wald foundation, Hamburg
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-naive 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-naive 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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