2. Academic Validation
  3. The CRTC1-MAML2 fusion is the major oncogenic driver in mucoepidermoid carcinoma

The CRTC1-MAML2 fusion is the major oncogenic driver in mucoepidermoid carcinoma

  • JCI Insight. 2021 Apr 8;6(7):e139497. doi: 10.1172/jci.insight.139497.
Zirong Chen 1 2,  Wei Ni 1 2 3,  Jian-Liang Li 4,  Shuibin Lin 1 2,  Xin Zhou 1 2,  Yuping Sun 5,  Jennifer W Li 6 7,  Marino E Leon 5,  Maria D Hurtado 8 9,  Sergei Zolotukhin 10,  Chen Liu 11,  Jianrong Lu 2 6,  James D Griffin 12,  Frederic J Kaye 2 7,  Lizi Wu 1 2 3
Affiliations

Affiliations

  • 1 Department of Molecular Genetics and Microbiology.
  • 2 UF Health Cancer Center, and.
  • 3 Genetics & Genomics Graduate Program, UF Genetics Institute, University of Florida College of Medicine, Gainesville, Florida, USA.
  • 4 Integrative Bioinformatics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
  • 5 Department of Pathology, Immunology and Laboratory Medicine.
  • 6 Department of Biochemistry and Molecular Biology, and.
  • 7 Department of Medicine, University of Florida College of Medicine, Gainesville, Florida, USA.
  • 8 Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, Mayo Clinic Health System La Crosse, Wisconsin, USA, and.
  • 9 Mayo Clinic, Rochester, Minnesota, USA.
  • 10 Department of Pediatrics, University of Florida College of Medicine, Gainesville, Florida, USA.
  • 11 Department of Pathology, Yale School of Medicine, Yale New Haven Hospital, New Haven, Connecticut, USA.
  • 12 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
PMID: 33830080 DOI: 10.1172/jci.insight.139497
Abstract

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.

Keywords

Head and neck cancer; Mouse models; Oncogenes; Oncology.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-50767
    99.94%, CDK4/6 Inhibitor
    CDK