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The CRTC1-MAML2 fusion is the major oncogenic driver in mucoepidermoid carcinoma
No effective systemic treatment is available for patients with unresectable, recurrent, or metastatic mucoepidermoid carcinoma (MEC), the most common salivary gland malignancy. MEC is frequently associated with a t(11;19)(q14-21;p12-13) translocation that creates a CRTC1-MAML2 fusion gene. The CRTC1...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119194/ https://www.ncbi.nlm.nih.gov/pubmed/33830080 http://dx.doi.org/10.1172/jci.insight.139497 |
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author | Chen, Zirong Ni, Wei Li, Jian-Liang Lin, Shuibin Zhou, Xin Sun, Yuping Li, Jennifer W. Leon, Marino E. Hurtado, Maria D. Zolotukhin, Sergei Liu, Chen Lu, Jianrong Griffin, James D. Kaye, Frederic J. Wu, Lizi |
author_facet | Chen, Zirong Ni, Wei Li, Jian-Liang Lin, Shuibin Zhou, Xin Sun, Yuping Li, Jennifer W. Leon, Marino E. Hurtado, Maria D. Zolotukhin, Sergei Liu, Chen Lu, Jianrong Griffin, James D. Kaye, Frederic J. Wu, Lizi |
author_sort | Chen, Zirong |
collection | PubMed |
description | No effective systemic treatment is available for patients with unresectable, recurrent, or metastatic mucoepidermoid carcinoma (MEC), the most common salivary gland malignancy. MEC is frequently associated with a t(11;19)(q14-21;p12-13) translocation that creates a CRTC1-MAML2 fusion gene. The CRTC1-MAML2 fusion exhibited transforming activity in vitro; however, whether it serves as an oncogenic driver for MEC establishment and maintenance in vivo remains unknown. Here, we show that doxycycline-induced CRTC1-MAML2 knockdown blocked the growth of established MEC xenografts, validating CRTC1-MAML2 as a therapeutic target. We further generated a conditional transgenic mouse model and observed that Cre-induced CRTC1-MAML2 expression caused 100% penetrant formation of salivary gland tumors resembling histological and molecular characteristics of human MEC. Molecular analysis of MEC tumors revealed altered p16-CDK4/6-RB pathway activity as a potential cooperating event in promoting CRTC1-MAML2–induced tumorigenesis. Cotargeting of aberrant p16-CDK4/6-RB signaling and CRTC1-MAML2 fusion–activated AREG/EGFR signaling with the respective CDK4/6 inhibitor Palbociclib and EGFR inhibitor Erlotinib produced enhanced antitumor responses in vitro and in vivo. Collectively, this study provides direct evidence for CRTC1-MAML2 as a key driver for MEC development and maintenance and identifies a potentially novel combination therapy with FDA-approved EGFR and CDK4/6 inhibitors as a potential viable strategy for patients with MEC. |
format | Online Article Text |
id | pubmed-8119194 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-81191942021-05-18 The CRTC1-MAML2 fusion is the major oncogenic driver in mucoepidermoid carcinoma Chen, Zirong Ni, Wei Li, Jian-Liang Lin, Shuibin Zhou, Xin Sun, Yuping Li, Jennifer W. Leon, Marino E. Hurtado, Maria D. Zolotukhin, Sergei Liu, Chen Lu, Jianrong Griffin, James D. Kaye, Frederic J. Wu, Lizi JCI Insight Research Article No effective systemic treatment is available for patients with unresectable, recurrent, or metastatic mucoepidermoid carcinoma (MEC), the most common salivary gland malignancy. MEC is frequently associated with a t(11;19)(q14-21;p12-13) translocation that creates a CRTC1-MAML2 fusion gene. The CRTC1-MAML2 fusion exhibited transforming activity in vitro; however, whether it serves as an oncogenic driver for MEC establishment and maintenance in vivo remains unknown. Here, we show that doxycycline-induced CRTC1-MAML2 knockdown blocked the growth of established MEC xenografts, validating CRTC1-MAML2 as a therapeutic target. We further generated a conditional transgenic mouse model and observed that Cre-induced CRTC1-MAML2 expression caused 100% penetrant formation of salivary gland tumors resembling histological and molecular characteristics of human MEC. Molecular analysis of MEC tumors revealed altered p16-CDK4/6-RB pathway activity as a potential cooperating event in promoting CRTC1-MAML2–induced tumorigenesis. Cotargeting of aberrant p16-CDK4/6-RB signaling and CRTC1-MAML2 fusion–activated AREG/EGFR signaling with the respective CDK4/6 inhibitor Palbociclib and EGFR inhibitor Erlotinib produced enhanced antitumor responses in vitro and in vivo. Collectively, this study provides direct evidence for CRTC1-MAML2 as a key driver for MEC development and maintenance and identifies a potentially novel combination therapy with FDA-approved EGFR and CDK4/6 inhibitors as a potential viable strategy for patients with MEC. American Society for Clinical Investigation 2021-04-08 /pmc/articles/PMC8119194/ /pubmed/33830080 http://dx.doi.org/10.1172/jci.insight.139497 Text en © 2021 Chen et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Chen, Zirong Ni, Wei Li, Jian-Liang Lin, Shuibin Zhou, Xin Sun, Yuping Li, Jennifer W. Leon, Marino E. Hurtado, Maria D. Zolotukhin, Sergei Liu, Chen Lu, Jianrong Griffin, James D. Kaye, Frederic J. Wu, Lizi The CRTC1-MAML2 fusion is the major oncogenic driver in mucoepidermoid carcinoma |
title | The CRTC1-MAML2 fusion is the major oncogenic driver in mucoepidermoid carcinoma |
title_full | The CRTC1-MAML2 fusion is the major oncogenic driver in mucoepidermoid carcinoma |
title_fullStr | The CRTC1-MAML2 fusion is the major oncogenic driver in mucoepidermoid carcinoma |
title_full_unstemmed | The CRTC1-MAML2 fusion is the major oncogenic driver in mucoepidermoid carcinoma |
title_short | The CRTC1-MAML2 fusion is the major oncogenic driver in mucoepidermoid carcinoma |
title_sort | crtc1-maml2 fusion is the major oncogenic driver in mucoepidermoid carcinoma |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119194/ https://www.ncbi.nlm.nih.gov/pubmed/33830080 http://dx.doi.org/10.1172/jci.insight.139497 |
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