Gefitinib Represses JAK-STAT Signaling Activated by CRTC1-MAML2 Fusion in Mucoepidermoid Carcinoma Cells

Author(s): Yufeng Wu, Zhen He, Shaomei Li, Hong Tang, Lili Wang, Sen Yang, Bing Dong, Jianjun Qin, Yue Sun, Han Yu, Yu Zhang, Yi Zhang, Yongjun Guo, Qiming Wang*.

Journal Name: Current Cancer Drug Targets

Volume 19 , Issue 10 , 2019

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Abstract:

Background: Gefitinib is well-known as a tyrosine kinase inhibitor targeting non-smalllung- 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.

Methods: To test this hypothesis, we developed a set of siRNAs to down-regulate C1-M2 expression. RNA-seq and Western blot techniques were applied to analyze the effects of gefitinib and siC1-M2 on the transcriptome of and the phosphorylation of tyrosine kinases in a MEC cell line H292.

Results: Deep-sequencing transcriptome analysis revealed that gefitinib extensively inhibited transcription of genes in JAK-STAT and MAPK/ERK pathways. 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.

Keywords: Gefitinib, CRTC1-MAML2 fusion, EGFR, JAK-STAT, mucoepidermoid carcinoma cells, phosphorylation.

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Article Details

VOLUME: 19
ISSUE: 10
Year: 2019
Page: [796 - 806]
Pages: 11
DOI: 10.2174/1568009619666190103122735
Price: $65

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