CDK4 and TERT amplification in head and neck mucosal melanoma.

Abstract

Recent high-throughput sequencing studies have revealed frequent CDK4 and TERT amplification in mucosal melanoma, suggesting that they are potential therapeutic targets. In this study, we investigated the statuses of CDK4 and TERT in head and neck mucosal melanoma (HNMM) with the aim of providing preclinical data to support future clinical trials. In total, 29 HNMM samples were collected, including 16 oral mucosal melanoma (OMM) samples and 13 nasal cavity/sinuses melanoma (SNMM) samples. Fluorescence in situ hybridization was used to analyze CDK4 and TERT amplification, and immunohistochemistry was used to analyze CDK4 and TERT protein expression patterns. CDK4 expression was knocked down in the ME cells (an OMM cell line), and changes in cell cycle were analyzed. Cell viability assays were performed to determine the sensitivity of ME to abemaciclib (a CDK4 inhibitor) combined with dacarbazine (an anti-melanoma chemotherapy drug). We detected five samples exhibited CDK4 amplifications and nine samples exhibited TERT amplifications in our HNMM series, and found that CDK4 amplification tended to occur in combination with TERT amplification. Amplifications of CDK4 and TERT were more common in OMM than in SNMM. Amplifications of CDK4 and TERT were associated with greater CDK4 and TERT protein expression levels. CDK4 knockdown led to delayed G1/S phase transition in ME cells. Furthermore, ME cells were sensitive to abemaciclib (IC50 =5.23nM). Abemaciclib and dacarbazine synergistically inhibited ME cells' viability. We confirmed high frequencies of CDK4 and TERT amplification in OMM. Combined therapy with a CDK4/6 inhibitor and anti-melanoma chemotherapeutic agents will be a reasonable strategy for future clinical trials concerning unresectable or metastatic OMM.