Targeting CREB-MYC Pathway Convergence in Salivary Mucoepidermoid Carcinoma
Objectives: Mucoepidermoid carcinomas (MECs) are frequently characterized by a CRTC1/MAML2 (C1/M2) fusion oncoprotein. We previously demonstrated that C1/M2 coordinately regulates CREB and MYC pathways via direct interactions. We aim to characterize the convergent pathways created by these interactions to aid in developing targeted therapies. Methods: Isogenic cells for inducible C1/M2 expression were used to dissect transcriptional changes and ChIP performed to determine direct C1/M2 recruitment. Bona fide MEC tumor cells lines were then used to validate findings and subsequently treated with small molecule drug inhibitors to target pathways identified. Results: Conditional C1/M2 expression revealed robust induction of IGF-1, a potent growth hormone involved in salivary gland homeostasis and regeneration. Analysis of MEC cells confirmed that C1/M2 fusion status correlates with robust IGF-1 levels, however ChIP revealed that C1/M2 does not directly bind and regulate the IGF-1 promoter. Rather, we uncovered a novel signaling circuit coordinated by C1/M2-CREB interactions that regulate a PPARγ Coactivator 1α (PGC-1α) variant that in turn drives IGF-1 expression. ChIP analysis confirmed C1/M2 binding to the PGC-1α promoter. Bioinformatics analyses identify MYC:MAX enrichment within the IGF-1R receptor promoter and this corresponds to increased IGF-1R transcript levels suggesting that C1/M2-CREB and C1/M2-MYC interactions establish an autocrine IGF-PI3K signal circuit. Consequently, MEC cell lines treated with the compound PPP (picropodophyllin), a selective inhibitor of the IGF-1 receptor (IGF-1R) but not of the insulin receptor, potently blocks C1/M2-driven MEC tumor cell growth. Conclusions: We discovered a novel C1/M2 – PGC-1α variant – IGF-1 – IGF-1R signaling circuit operational in C1/M2 fusion positive MEC and confirm that MEC cells are dependent on this circuit for growth providing evidence for a promising strategy to therapeutically target MEC. Ongoing studies are evaluating the use of FDA-approved drugs that target IGF-1R alone or in combination with drugs targeting other downstream nodes within this C1/M2 – PGC-1α variant – IGF-1 – IGF-1R signal circuit.
AADR/CADR Annual Meeting
2018 AADR/CADR Annual Meeting (Fort Lauderdale, Florida) Fort Lauderdale, Florida
2018 0063 Oral Medicine & Pathology Research
Musicant, Adele M
( The University of North Carolina at Chapel Hill
, Chapel Hill
, North Carolina
, United States
)
Sharma, Kshitji
( The University of North Carolina at Chapel Hill
, Chapel Hill
, North Carolina
, United States
)
Aghera, Shaily
( The University of North Carolina at Chapel Hill
, Chapel Hill
, North Carolina
, United States
)
Henry, Erin
( The University of North Carolina at Chapel Hill
, Chapel Hill
, North Carolina
, United States
)
Kaye, Frederic
( University of Florida College of Medicine
, Gainesville
, Florida
, United States
)
Flaveny, Colin
( Saint Louis University School of Medicine
, Saint Louis
, Missouri
, United States
)
Amelio, Antonio
( The University of North Carolina at Chapel Hill
, Chapel Hill
, North Carolina
, United States
)
Supported by NIGMS Genetics Training Grant Award 5T32 GM007092, NCI Pathway to Independence Award R00-CA157954, UNC Dental Foundation, and UNC University Cancer Research Funds.
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