TY - JOUR
T1 - Intrinsic cell-penetrating activity propels omomyc from proof of concept to viable anti-myc therapy
AU - Beaulieu, Marie Eve
AU - Jauset, Toni
AU - Massó-Vallés, Daniel
AU - Martínez-Martín, Sandra
AU - Rahl, Peter
AU - Maltais, Loïka
AU - Zacarias-Fluck, Mariano F.
AU - Casacuberta-Serra, Sílvia
AU - Del Pozo, Erika Serrano
AU - Fiore, Christopher
AU - Foradada, Laia
AU - Cano, Virginia Castillo
AU - Sánchez-Hervás, Meritxell
AU - Guenther, Matthew
AU - Sanz, Eduardo Romero
AU - Oteo, Marta
AU - Tremblay, Cynthia
AU - Martín, Génesis
AU - Letourneau, Danny
AU - Montagne, Martin
AU - Alonso, Miguel Ángel Morcillo
AU - Whitfield, Jonathan R.
AU - Lavigne, Pierre
AU - Soucek, Laura
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
U2 - 10.1126/scitranslmed.aar5012
DO - 10.1126/scitranslmed.aar5012
M3 - Article
C2 - 30894502
VL - 11
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
M1 - eaar5012
ER -