Abstract
Cetuximab is a widely used drug for treating head and neck squamous cell carcinomas (HNSCCs); however, it provides restricted clinical benefits, and its response duration is limited by drug resistance. Here, we conducted randomized “Phase II-like clinical trials” of 49 HNSCC PDX models and reveal multiple informative biomarkers for intrinsic resistance to cetuximab (e.g., amplification of ANKH, up-regulation of PARP3). After validating these intrinsic resistance biomarkers in another HNSCC PDX cohort (61 PDX models), we generated acquired cetuximab resistance PDX models and analyzed them to uncover resistance mechanisms. Whole exome sequencing and transcriptome sequencing revealed diverse patterns of clonal selection in acquired resistant PDXs, including the emergence of subclones with strongly activated RAS/MAPK. Extending these insights, we show that a combination of a RAC1/RAC3 dual-target inhibitor and cetuximab could overcome acquired cetuximab resistance in vitro and in vivo. Beyond revealing intrinsic resistance biomarkers, our PDX-based study shows how clonal architecture changes underlying acquired resistance can be targeted to expand the therapeutic utility of this important drug to more HNSCC patients.
Highlights
Head and neck squamous cell carcinomas (HNSCCs) develop from the mucosal epithelium in the oral cavity, pharynx, and larynx and are the most common malignancies that arise in the head and neck
We undertook efforts aiming to build a biobank of surgical anti-Epidermal growth factor receptor (EGFR) therapy, HNSCC_489 exhibited clinical benefit materials from HNSCC patients, which were stored under viable (−52.12%) and HNSCC_545 had a modest tumor response conditions and serially propagated in mouse recipients
The results showed that HNSCC Patient-derived xenograft (PDX) exhibit a high be recapitulated in our PDX clinical trial (PCT)
Summary
Head and neck squamous cell carcinomas (HNSCCs) develop from the mucosal epithelium in the oral cavity, pharynx, and larynx and are the most common malignancies that arise in the head and neck. Epidermal growth factor receptor (EGFR) is amplified and overexpressed in most (≥80%) HNSCC tumors, and is associated with more aggressive disease and poorer prognosis.[1]. Cetuximab is a chimeric EGFR IgG1 monoclonal antibody (mAb) approved in combination with radiation therapy for the treatment of locally advanced HNSCCs, and in combination with platinum-based chemotherapy for treatment of recurrent and/or metastatic HNSCCs.[2,3]. Despite the improvement in clinical outcomes for HNSCCs as the result of cetuximab combination therapies, intrinsic or acquired resistance increases tumor recurrence rates and limits clinical efficacy.[4]. The treatment efficacy of cetuximab is low, with an objective response rate of 13% in the monotherapy setting[2] and 36% in combination with chemotherapy.[5]. Time-totreatment failure in patients treated with the EXTREME regimen ranges only around 5 months despite cetuximab maintenance.[4,6]
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