The TCGA database was analyzed to identify deregulation of cell cycle genes across 24
cancer types and ensuing effects on patient survival. Pan-
cancer analysis showed that
head and neck squamous cell carcinoma (
HNSCC) ranks amongst the top four
cancers showing deregulated cell cycle genes. Also, the median gene expression of all CDKs and
cyclins in
HNSCC patient samples was higher than that of the global gene expression. This was verified by IHC staining of CCND1 from
HNSCC patients. When evaluating the quartiles with highest and lowest expression, increased CCND1/CDK6 levels had negative implication on patient survival. In search for a
drug, which may antagonize this
tumor profile, the potential of the alkylphosphocholine
erufosine was evaluated against cell lines of the
HNSCC subtype,
oral squamous cell carcinoma (OSCC) using in-vitro and in-vivo assays.
Erufosine inhibited growth of OSCC cell lines concentration dependently. Initial microarray findings revealed that
cyclins and CDKs were down-regulated concentration dependently upon exposure to
erufosine and participated in negative enrichment of cell cycle processes. These findings, indicating a pan-cdk/
cyclin inhibition by
erufosine, were verified at both,
mRNA and
protein levels.
Erufosine caused a G2/M block and inhibition of colony formation. Significant
tumor growth retardation was seen upon treatment with
erufosine in a xenograft model. For the decreased
cyclin D1 and CDK 4/6 levels found in
tumor tissue, these
proteins can serve as
biomarker for
erufosine intervention. The findings demonstrate the potential of
erufosine as cell cycle inhibitor in
HNSCC treatment, alone or in combination with current therapeutic agents.