Journal Article

Aberrantly activated AREG–EGFR signaling is required for the growth and survival of CRTC1–MAML2 fusion-positive mucoepidermoid carcinoma cells

Cao, C, Griffin, J D, Chen, Z, Lin, S, Wu, L, Li, J, Gu, Y, Shen, H, Ha, P K, Hu, C, Chen, J, Li, J-L, Gao, R, Kaye, F J

2014

Overview

Salivary gland tumors (SGT) are a group of highly heterogeneous head and neck malignancies with widely varied clinical outcomes and no standard effective treatments. The CRTC1–MAML2 fusion oncogene, encoded by a recurring chromosomal translocation t(11;19)(q14-21;p12-13), is a frequent genetic alteration found in >50% of mucoepidermoid carcinomas (MEC), the most common malignant SGT. In this study, we aimed to define the role of the CRTC1–MAML2 oncogene in the maintenance of MEC tumor growth and to investigate critical downstream target genes and pathways for therapeutic targeting of MEC. By performing gene expression analyses and functional studies via RNA interference and pharmacological modulation, we determined the importance of the CRTC1–MAML2 fusion gene and its downstream AREG–EGFR signaling in human MEC cancer cell growth and survival in vitro and in vivo using human MEC xenograft models. We found that CRTC1–MAML2 fusion oncogene was required for the growth and survival of fusion-positive human MEC cancer cells in vitro and in vivo . The CRTC1–MAML2 oncoprotein induced the upregulation of the epidermal growth factor receptor (EGFR) ligand Amphiregulin (AREG) by co-activating the transcription factor CREB, and AREG subsequently activated EGFR signaling in an autocrine manner that promoted MEC cell growth and survival. Importantly, CRTC1–MAML2-positive MEC cells were highly sensitive to EGFR signaling inhibition. Therefore, our study revealed that aberrantly activated AREG–EGFR signaling is required for CRTC1–MAML2-positive MEC cell growth and survival, suggesting that EGFR-targeted therapies will benefit patients with advanced, unresectable CRTC1–MAML2-positive MEC.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/67/1536 / 631/80/86 / Amphiregulin / Animals / Antibodies, Monoclonal, Humanized - pharmacology / Apoptosis / Autocrine signalling / Cancer / Cancer cells / Cancer therapies / Carcinoma / Carcinoma, Mucoepidermoid - genetics / Carcinoma, Mucoepidermoid - metabolism / Cell Biology / Cell fusion / Cell growth / Cell Line, Tumor / Cell Proliferation - drug effects / Cell survival / Cell Survival - drug effects / Cell Survival - genetics / Cellular signal transduction / Cetuximab / Chromosome translocations / Chromosomes, Human, Pair 11 / Chromosomes, Human, Pair 19 / Clinical outcomes / Cyclic AMP response element-binding protein / Cyclic AMP Response Element-Binding Protein - metabolism / Disease Models, Animal / DNA-Binding Proteins - genetics / EGF Family of Proteins / Epidermal growth factor / Epidermal growth factor receptors / Female / Fusion protein / Gene expression / Gene Expression Regulation, Neoplastic / Genetic aspects / Glycoproteins - genetics / Glycoproteins - metabolism / Head & neck cancer / Heterografts / Human Genetics / Humans / Intercellular Signaling Peptides and Proteins - genetics / Intercellular Signaling Peptides and Proteins - metabolism / Internal Medicine / Kinases / Medicine / Medicine & Public Health / Nuclear Proteins - genetics / Oncogene Proteins, Fusion - genetics / Oncogene Proteins, Fusion - metabolism / Oncology / Oral cancer / original-article / Physiological aspects / Protein Binding / Receptor, Epidermal Growth Factor - antagonists & inhibitors / Receptor, Epidermal Growth Factor - metabolism / RNA-mediated interference / Salivary gland / Salivary gland tumors / Signal transduction / Signal Transduction - drug effects / Therapeutic targets / Transcription Factors - genetics / Transcriptional Activation / Translocation, Genetic / Xenografts