Intrinsic cell-penetrating activity propels omomyc from proof of concept to viable anti-myc therapy

Marie Eve Beaulieu, Toni Jauset, Daniel Massó-Vallés, Sandra Martínez-Martín, Peter Rahl, Loïka Maltais, Mariano F. Zacarias-Fluck, Sílvia Casacuberta-Serra, Erika Serrano Del Pozo, Christopher Fiore, Laia Foradada, Virginia Castillo Cano, Meritxell Sánchez-Hervás, Matthew Guenther, Eduardo Romero Sanz, Marta Oteo, Cynthia Tremblay, Génesis Martín, Danny Letourneau, Martin MontagneMiguel Ángel Morcillo Alonso, Jonathan R. Whitfield, Pierre Lavigne, Laura Soucek

Research output: Contribution to journalArticleResearch

43 Citations (Scopus)

Abstract

Copyright © 2019 The Authors, some rights reserved. Inhibiting MYC has long been considered unfeasible, although its key role in human cancers makes it a desirable target for therapeutic intervention. One reason for its perceived undruggability was the fear of catastrophic side effects in normal tissues. However, we previously designed a dominant-negative form of MYC called Omomyc and used its conditional transgenic expression to inhibit MYC function both in vitro and in vivo. MYC inhibition by Omomyc exerted a potent therapeutic impact in various mouse models of cancer, causing only mild, well-tolerated, and reversible side effects. Nevertheless, Omomyc has been so far considered only a proof of principle. In contrast with that preconceived notion, here, we show that the purified Omomyc mini-protein itself spontaneously penetrates into cancer cells and effectively interferes with MYC transcriptional activity therein. Efficacy of the Omomyc mini-protein in various experimental models of non-small cell lung cancer harboring different oncogenic mutation profiles establishes its therapeutic potential after both direct tissue delivery and systemic administration, providing evidence that the Omomyc mini-protein is an effective MYC inhibitor worthy of clinical development.
Original languageEnglish
Article numbereaar5012
JournalScience Translational Medicine
Volume11
DOIs
Publication statusPublished - 1 Jan 2019

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