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. By reducing MYC's transcriptional footprint in melanoma, Omomyc elicits gene expression profiles remarkably similar to those of patients with good prognosis, underlining the therapeutic potential that such an approach could eventually have in the clinic in this dismal disease.

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

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. Here we demonstrate for the first time that MYC inhibition by transgenic Omomyc is efficacious against all breast cancer molecular subtypes, including triple-negative breast cancer, where it displays potent antimetastatic properties both in vitro and in vivo. Importantly, pharmacologic treatment with the recombinantly produced Omomyc miniprotein, recently entering a clinical trial in solid tumors, recapitulates several key features of expression of the Omomyc transgene, confirming its clinical applicability to metastatic breast cancer, including advanced triple-negative breast cancer, a disease in urgent need of better therapeutic options. Significance: While MYC role in metastasis has been long controversial, this manuscript demonstrates that MYC inhibition by either transgenic expression or pharmacologic use of the recombinantly produced Omomyc miniprotein exerts antitumor and antimetastatic activity in breast cancer models in vitro and in vivo, suggesting its clinical applicability.