1. Academic Validation
  2. 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.
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
    99.96%, CDK4/6 Inhibitor
    CDK