Gefitinib represses JAK-STAT signaling activated by CRTC1-MAML2 fusion in mucoepidermoid carcinoma cells.

BACKGROUND: Gefitinib is well-known as a tyrosine kinase inhibitor targeting non-small-lung-cancer (NSCLC) containing EGFR mutations. However, its effectiveness in treating mucoepidermoid carcinoma (MEC) without such EGFR mutations suggests additional targets.

OBJECTIVE: The CRTC1-MAML2 (C1-M2) fusion typical for MEC has been proposed to be a gefitinib target.

METHOD: To test this hypothesis, we developed a set of siRNAs to down-regulate C1-M2 expression. Deep-sequencing transcriptome analysis revealed that gefitinib extensively inhibited transcription of genes in JAK-STAT and MAPK/ERK pathways.

RESULTS: Both siC1-M2 and gefitinib inhibited the phosphorylation of multiple signaling kinases in these signaling pathways, indicating that gefitinib inhibited JAK-STAT and MAPK/ERK pathways activated by C1-M2 fusion. Moreover, gefitinib inhibition of EGFR and MAPK/ERK was more effective than that of AKT, JAK2 and STATs, and their dependence on C1-M2 could be uncoupled. Taken together, our results suggest that gefitinib simultaneously represses phosphorylation of multiple key signaling proteins which are activated in MEC, in part by C1-M2 fusion. Gefitinib-repressed kinase phosphorylation explains the transcriptional repression of genes in JAK-STAT and MAPK/ERK pathways.

CONCLUSION: These findings provide new insights into the efficacy of gefitinib in treating mucoepidermoid carcinoma, and suggest that a combination of gefitinib and other inhibitors specifically against C1-M2 fusion could be more effective.