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.
Highlights
Fusion cancer genes are unique diagnostic and therapeutic biomarkers due to their selective expression in specific tumor subtypes and their detection as core somatic mutational events that predict an early role in initiation of tumorigenesis [1,2,3]
Doxycycline-induced CRTC1-MAML2 knockdown blocks the growth of established Mucoepidermoid carcinoma (MEC) tumors
We previously showed that CRTC1-MAML2 induced an autocrine AREG-EGFR signaling and that blocking this aberrant EGFR signaling reduced MEC growth and survival [32], indicating that the identification of the CRTC1-MAML2–induced pathogenic signaling could provide potential rational therapeutic strategies
Summary
Fusion cancer genes are unique diagnostic and therapeutic biomarkers due to their selective expression in specific tumor subtypes and their detection as core somatic mutational events that predict an early role in initiation of tumorigenesis [1,2,3]. A recurrent t(11;19)(q14-21;p12-13) translocation encoding a potentially novel CRTC1-MAML2 gene fusion has been detected in up to 80% of MEC cases in studies of multiple cohorts [15,16,17,18]. The t(11;19) translocation is occasionally the sole cytogenetic alteration in MEC salivary gland tumors [23] and is detected in nonsalivary gland MEC–like tumors throughout the body [8, 10], suggesting that the acquired CRTC1-MAML2 fusion is an early core event in MEC pathogenesis. A comprehensive understanding of mechanisms of CRTC1-MAML2–mediated tumorigenesis and requirements for sequential cooperating somatic events will be critical for development of effective treatments
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