Abstract
The use of EGFR inhibitors on oral squamous cell carcinoma (OSCC) as monotherapy yielded modest clinical outcomes and therefore would benefit from biomarkers that could predict which patient subsets are likely to respond. Here, we determined the efficacy of erlotinib in OSCC cell lines, and by comparing sensitive and resistant lines to identify potential biomarkers. We focused on the 4717C > G polymorphism in periplakin (PPL) where the CC genotype was associated with erlotinib resistance. To validate this, erlotinib-resistant cell lines harbouring CC genotype were engineered to overexpress the GG genotype and vice versa. Isogenic cell lines were then studied for their response to erlotinib treatment. We demonstrated that overexpression of the GG genotype in erlotinib-resistant lines sensitized them to erlotinib and inhibition of AKT phosphorylation. Similarly, the expression of the CC genotype conferred resistance to erlotinib with a concomitant increase in AKT phosphorylation. We also demonstrated that cell lines with the CC genotype generally are more resistant to other EGFR inhibitors than those with the GG genotype. Overall, we showed that a specific polymorphism in the PPL gene could confer resistance to erlotinib and other EGFR inhibitors and further work to evaluate these as biomarkers of response is warranted.
Highlights
Oral squamous cell carcinoma is one of the top ten cancers among men in the world[1]
Detail analysis showed that 52% of patients treated with erlotinib and cisplatin had a complete response as compared to 40% of patients who responded to cisplatin alone[11]; for gefitinib, 12.5% of patients who received docetaxel and gefitinib showed response as compared to 6.2% for patients treated with docetaxel alone[12]
Focusing primarily on the epidermal growth factor receptor (EGFR) inhibitor erlotinib, we demonstrated that a single nucleotide polymorphism (SNP) in PPL could inhibit AKT phosphorylation and modulate response to erlotinib
Summary
Oral squamous cell carcinoma is one of the top ten cancers among men in the world[1]. The success of cetuximab, a recombinant monoclonal antibody targeting EGFR in extending the progression-free survival (PFS) in patients with recurrent/metastatic OSCC, resulted in its approval by US Food and Drug Administration (FDA) in 20067. Whilst this is encouraging, this success has not been recapitulated with small molecule inhibitors targeting EGFR. Erlotinib is an orally active small molecule that blocks EGFR-mediated intracellular signalling by binding competitively to the ATP binding region[8] It is approved for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with stable disease after standard platinum-based first-line chemotherapy[9]. Focusing primarily on the EGFR inhibitor erlotinib, we demonstrated that a single nucleotide polymorphism (SNP) in PPL could inhibit AKT phosphorylation and modulate response to erlotinib
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