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.
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http://dx.doi.org/10.1172/jci.insight.139497 | DOI Listing |
Oral Oncol
December 2024
Department of Otolaryngology - Head and Neck Surgery, University of Michigan, Ann Arbor, MI, USA; Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI, USA; Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. Electronic address:
NPJ Precis Oncol
October 2024
Department of Oral Pathology, Peking University School and Hospital of Stomatology & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, PR China.
Oral Oncol
December 2024
School of Clinical Dentistry, University of Sheffield, Sheffield, United Kingdom. Electronic address:
Objectives: Mucoepidermoid carcinoma (MEC) is the most common malignant salivary gland tumour with around 50 % of cases carrying the CRTC1-MAML2 translocation. The CREB pathway has been associated with the transforming activity of this translocation. The aim of this study was to determine the effects of CREB inhibition on MEC cell behaviour in vitro.
View Article and Find Full Text PDFDiagn Pathol
January 2024
Department of Pathology, Guangdong Provincial People's Hospital/Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China.
Am J Surg Pathol
October 2023
CARADERM, French Network of Rare Cutaneous Cancer.
Recurrent oncogenic drivers have been identified in a variety of sweat gland tumors. Recently, integration of human papillomavirus type 42 (HPV42) has been reported in digital papillary adenocarcinoma (DPA). The main objectives of the present study were (i) to provide an overview of the prevalence of previously identified oncogenic drivers in acral sweat gland tumors and (ii) to genetically characterize tumors in which no recurrent genetic alteration has been identified yet.
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