Abstract
Cetuximab, an antibody directed against the EGF receptor, is an effective clinical therapy for patients with head and neck squamous cell cancer (HNSCC). Despite great clinical promise, intrinsic or acquired cetuximab resistance hinders successful treatment outcomes but little is known about the underlying mechanism. To study the role of oncogenic HRAS in cetuximab resistance in HNSCC, the frequency of oncogenic HRAS mutations was determined in a cohort of 180 genomic DNAs from head and neck cancer specimens. We also used a combination of cetuximab-resistant cell lines and a transgenic mouse model of RAS-driven oral cancer to identify an oncogenic RAS-specific gene expression signature that promotes cetuximab resistance. Here, we show that activation of RAS signaling leads to persistent extracellular signal-regulated kinase 1/2 signaling and consequently to cetuximab resistance. HRAS depletion in cells containing oncogenic HRAS or PIK3CA restored cetuximab sensitivity. In our study, the gene expression signature of c-MYC, BCL-2, BCL-XL, and cyclin D1 upon activation of MAPK signaling was not altered by cetuximab treatment, suggesting that this signature may have a pivotal role in cetuximab resistance of RAS-activated HNSCC. Finally, a subset of patients with head and neck cancer with oncogenic HRAS mutations was found to exhibit de novo resistance to cetuximab-based therapy. Collectively, these findings identify a distinct cetuximab resistance mechanism. Oncogenic HRAS in HNSCC promotes activation of ERK signaling, which in turn mediates cetuximab resistance through a specific gene expression signature. Clin Cancer Res; 20(11); 2933-46. ©2014 AACR.
Highlights
The EGF receptor (EGFR) signaling pathway is commonly activated in head and neck squamous cell carcinoma (HNSCC) and represents a validated target for therapy
The gene expression signature of c-MYC, BCL-2, BCL-XL, and cyclin D1 upon activation of mitogen-activated protein kinase (MAPK) signaling was not altered by cetuximab treatment, suggesting that this signature may have a pivotal role in cetuximab resistance of RAS-activated HNSCC
The gene expression signature of C-myc, BCL-2, BCL-XL, and cyclin D1 upon activation of MAPK signaling was not altered by cetuximab treatment, suggesting that this signature may have a pivotal role in cetuximab resistance of RAS activated HNSCC
Summary
HRAS is frequently mutated in HNSCC A total of 180 Formalin-Fixed, Paraffin-Embedded (FFPE). Treatment with 25 nmol/L cetuximab caused a 55% and 50% growth suppression to the mock-infected UM-SCC1 and UM-SCC25 cells, respectively, compared with their G12V HRAS–expressing cells Overall, these findings indicate that head and neck cancer cells with oncogenic RAS signaling exhibit an aggressive phenotype, which is characterized by cetuximab resistance and enhanced invasion potential. Quantitative real time PCR analysis confirmed that the gene expression profile of c-myc, cyclin D1, and BCL-XL was unaffected by cetuximab treatment in cells with oncogenic HRAS expression and revealed that c-myc upregulation is mediated by both posttranslational modifications (phosphorylation on threonine 58 and serine 62) and transcriptional activation (Fig. 6B) Taken together, these data suggest that the expression signature of G12V HRAS about c-myc, BCL-XL and cyclin D1 in HNSCC is not altered by cetuximab treatment.
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