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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2021-04-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.139497 |
| _version_ | 1818356102701514752 |
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| author | Zirong Chen Wei Ni Jian-Liang Li Shuibin Lin Xin Zhou Yuping Sun Jennifer W. Li Marino E. Leon Maria D. Hurtado Sergei Zolotukhin Chen Liu Jianrong Lu James D. Griffin Frederic J. Kaye Lizi Wu |
| author_facet | Zirong Chen Wei Ni Jian-Liang Li Shuibin Lin Xin Zhou Yuping Sun Jennifer W. Li Marino E. Leon Maria D. Hurtado Sergei Zolotukhin Chen Liu Jianrong Lu James D. Griffin Frederic J. Kaye Lizi Wu |
| author_sort | Zirong Chen |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-13T19:51:53Z |
| format | Article |
| id | doaj.art-965ab914f0fd46c8b8ed2810d62f17db |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-12-13T19:51:53Z |
| publishDate | 2021-04-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-965ab914f0fd46c8b8ed2810d62f17db2022-12-21T23:33:24ZengAmerican Society for Clinical investigationJCI Insight2379-37082021-04-0167The CRTC1-MAML2 fusion is the major oncogenic driver in mucoepidermoid carcinomaZirong ChenWei NiJian-Liang LiShuibin LinXin ZhouYuping SunJennifer W. LiMarino E. LeonMaria D. HurtadoSergei ZolotukhinChen LiuJianrong LuJames D. GriffinFrederic J. KayeLizi WuNo 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.https://doi.org/10.1172/jci.insight.139497Oncology |
| spellingShingle | Zirong Chen Wei Ni Jian-Liang Li Shuibin Lin Xin Zhou Yuping Sun Jennifer W. Li Marino E. Leon Maria D. Hurtado Sergei Zolotukhin Chen Liu Jianrong Lu James D. Griffin Frederic J. Kaye Lizi Wu The CRTC1-MAML2 fusion is the major oncogenic driver in mucoepidermoid carcinoma JCI Insight Oncology |
| 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 | Oncology |
| url | https://doi.org/10.1172/jci.insight.139497 |
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