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.
Highlights
Head and neck squamous cell carcinomas (HNSCC) arising in the larynx, pharynx, oral cavity, paranasal sinuses and nasal cavity are among the most common types of cancers, accounting for almost 60,000 newly diagnosed cases and more than 10,000 estimated deaths per year in the United States alone [1]
Little is known so far about the molecular mechanisms underlying clinical resistance and we currently lack appropriate biomarkers that could help in identifying patient subsets that are either likely or unlikely to derive benefit from this epidermal growth factor receptor (EGFR)-targeted therapy or from prolonged antibody treatment in a cetuximab maintenance setting
In this study we focused on potential modifications of the EGFR ectodomain that may interfere with antibody binding and activating mutations of RAS, which are known to confer resistance in metastatic colorectal cancer [10, 19]
Summary
Head and neck squamous cell carcinomas (HNSCC) arising in the larynx, pharynx, oral cavity, paranasal sinuses and nasal cavity are among the most common types of cancers, accounting for almost 60,000 newly diagnosed cases and more than 10,000 estimated deaths per year in the United States alone [1]. Constitutive RAS signaling is mediated by mutations that prevent GTP hydrolysis, locking RAS in a permanently active state, independent of EGFR engagement For this reason, colon tumors harboring activating RAS mutations do not respond to EGFR targeting and mutational screening is routinely used for patient selection prior to treatment [11, 12]. The extracellular domain mutations R451C, S464L, G465R, K467T, I491M and S492R of the EGFR (all located in exon 12) were found in post-therapeutic tumor subclones or antibody-resistant cell lines by next-generation or sanger sequencing These mutations abrogated antibody binding and, resulted in clinical resistance to cetuximab and/or panitumumab depending on their localization within the antibody epitopes [17, 19]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
