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

[ Vol. 19 , Issue. ]

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 and Qiming WangPages 1-1 (1)

Abstract:


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.

Keywords:

gefitinib, CRTC1-MAML2 fusion, JAK-STAT, EGFR, mucoepidermoid carcinoma cells

Affiliation:

Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, 450008, Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, 450008, Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, 450008, Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, 450008, Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, 450008, Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, 450008, Department of Molecular Pathology, the Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, 450008, Department of Thoracic surgery, the Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, 450008, Laboratory of Human Health and Genome Regulation, and Center for Genome Analysis, ABLife Inc., Wuhan, Hubei 430075, Laboratory of Human Health and Genome Regulation, and Center for Genome Analysis, ABLife Inc., Wuhan, Hubei 430075, Laboratory of Human Health and Genome Regulation, and Center for Genome Analysis, ABLife Inc., Wuhan, Hubei 430075, Laboratory of Human Health and Genome Regulation, and Center for Genome Analysis, ABLife Inc., Wuhan, Hubei 430075, Department of Molecular Pathology, the Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, 450008, Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, 450008



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