Genetic and Expression Profiles of Squamous Cell Carcinoma of the Head and Neck Correlate with Cisplatin Sensitivity and Resistance in Cell Lines and Patients

Abstract

Purpose: The choice of treatment for squamous cell carcinoma of the head and neck (SCCHN) is still primarily based on the tumor-node-metastasis classification. However, it is reasonable to believe that biological profiles of SCCHN may be independently associated with response to therapy. The aim of the present study was to examine genetic changes and gene expression profiles that might correlate with sensitivity to cisplatin [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay] in 10 SCCHN cell lines.Experimental Design: Five cisplatin-sensitive and five cisplatin-resistant cell lines [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay] were studied by comparative genomic hybridization, spectral karyotyping, and cDNA microarray analysis (21,632 sequence-validated human cDNA; confirmation by reverse transcriptase-PCR for selected genes). For the MET proto-oncogene, which showed low expression in the chemosensitive cell lines, we did immunohistochemical staining on SCCHN of 29 patients who received induction chemotherapy.Results: The five cisplatin-resistant cell lines showed significantly more genetic imbalances (regions of loss and amplification) and chromosomal abnormalities by comparative genomic hybridization and spectral karyotyping, respectively, than did the five cisplatin-sensitive cell lines. Microarray studies identified ϳ60 genes that clearly distinguish between the two groups of cell lines. Some of these genes are known to be involved in tumor progression, metastasis, and drug resistance. We identified low expression of c-met (immunohistochemistry) as a predictive factor for complete response in nondiploid tumors (P ‫؍‬ 0.026).Conclusions: We conclude that cisplatin sensitivity and resistance are related to distinctive differences in the genetic and expression profiles in individual SCCHN tumor cell lines and in SCCHN patients. The genes we have identified may serve as potential targets for novel treatment strategies.

A Novel Nuclear Factor-κB Gene Signature Is Differentially Expressed in Head and Neck Squamous Cell Carcinomas in Association with TP53 Status

“…Interestingly, when we further analyzed the preferred binding motifs for different NF-nB subunits, a predominance of p65 binding motifs were observed in the promoters of cluster B genes, in contrast to the prevalence of p50 and c-REL binding motifs present in the promoters of cluster A genes with putative NFnB binding sites. 5 Significant differences in the prevalence of TP53 and NF-nB p65 binding sites were detected between clusters A and B (Fig. 3C, m 2 , P < 0.05).…”

“…In head and neck squamous cell carcinomas (HNSCC), gene expression profiling has been used in an attempt to identify biomarker signatures for diagnosis (4), differential sensitivity to chemotherapy (5), risk of recurrence (6), survival (7), malignant phenotype (8), and metastasis (9). Although considerable variability in the composition of gene signatures was observed in these studies, the data provided evidence for subsets and heterogeneity within HNSCC, which are possibly related to differences in molecular pathogenesis and malignant potential.…”

Gene expression response to cisplatin treatment in drug-sensitive and drug-resistant ovarian cancer cells

“…In addition, these techniques have also allowed for the identification of gene expression signatures that may help predict cisplatin sensitivity in various cancers (Akervall et al, 2004;Takata et al, 2005).…”

Proteasome Inhibitor PS-341 Induces Apoptosis in Cisplatin-resistant Squamous Cell Carcinoma Cells by Induction of Noxa

“…Unfortunately, significant numbers of resistant SCC cells emerge rapidly following initial cisplatin treatment. Thus, many retrospective clinical studies reported that cisplatin was unable to increase survival when administered as a monotherapy or in combination with surgery or radiotherapy (11)(12)(13). Cisplatin is a platinum-containing compound that induces DNA damage by binding to DNA and forming adducts that impair de novo synthesis.…”