Reducing MYC's transcriptional footprint unveils a good prognostic gene signature in melanoma.

MYC's key role in oncogenesis and tumor progression has long been established for most human cancers. In melanoma, its deregulated activity by amplification of 8q24 chromosome or by upstream signaling coming from activating mutations in the RAS/RAF/MAPK pathway-the most predominantly mutated pathway in this disease-turns MYC into not only a driver but also a facilitator of melanoma progression, with documented effects leading to an aggressive clinical course and resistance to targeted therapy. Here, by making use of Omomyc, the most characterized MYC inhibitor to date that has just successfully completed a phase I clinical trial, we show for the first time that MYC inhibition in melanoma induces remarkable transcriptional modulation, resulting in severely compromised tumor growth and a clear abrogation of metastatic capacity independently of the driver mutation.

MYC Inhibition Halts Metastatic Breast Cancer Progression by Blocking Growth, Invasion, and Seeding.

Unlabelled: MYC's role in promoting tumorigenesis is beyond doubt, but its function in the metastatic process is still controversial. Omomyc is a MYC dominant negative that has shown potent antitumor activity in multiple cancer cell lines and mouse models, regardless of their tissue of origin or driver mutations, by impacting on several of the hallmarks of cancer. However, its therapeutic efficacy against metastasis has not been elucidated yet.

Pharmacokinetic Analysis of Omomyc Shows Lasting Structural Integrity and Long Terminal Half-Life in Tumor Tissue.

MYC is an oncoprotein causally involved in the majority of human cancers and a most wanted target for cancer treatment. Omomyc is the best-characterized MYC dominant negative to date. In the last years, it has been developed into a therapeutic miniprotein for solid tumor treatment and recently reached clinical stage.

The Wnt signaling receptor Fzd9 is essential for Myc-driven tumorigenesis in pancreatic islets.

The huge cadre of genes regulated by Myc has obstructed the identification of critical effectors that are essential for Myc-driven tumorigenesis. Here, we describe how only the lack of the receptor Fzd9, previously identified as a Myc transcriptional target, impairs sustained tumor expansion and β-cell dedifferentiation in a mouse model of Myc-driven insulinoma, allows pancreatic islets to maintain their physiological structure and affects Myc-related global gene expression. Importantly, Wnt signaling inhibition in Fzd9-competent mice largely recapitulates the suppression of proliferation caused by Fzd9 deficiency upon Myc activation.