Signature-driven repurposing of Midostaurin for combination with MEK1/2 and KRASG12C inhibitors in lung cancer

• Published in: Nature Communications
• Main Authors: Irati Macaya, Marta Roman, Connor Welch, Rodrigo Entrialgo-Cadierno, Marina Salmon, Alba Santos, Iker Feliu, Joanna Kovalski, Ines Lopez, Maria Rodriguez-Remirez, Sara Palomino-Echeverria, Shane M. Lonfgren, Macarena Ferrero, Silvia Calabuig, Iziar A. Ludwig, David Lara-Astiaso, Eloisa Jantus-Lewintre, Elizabeth Guruceaga, Shruthi Narayanan, Mariano Ponz-Sarvise, Antonio Pineda-Lucena, Fernando Lecanda, Davide Ruggero, Purvesh Khatri, Enrique Santamaria, Joaquin Fernandez-Irigoyen, Irene Ferrer, Luis Paz-Ares, Matthias Drosten, Mariano Barbacid, Ignacio Gil-Bazo, Silve Vicent
• Format: Article
• Language: English
• Published: Nature Portfolio 2023-10-01
• Online Access: https://doi.org/10.1038/s41467-023-41828-z

Abstract Drug combinations are key to circumvent resistance mechanisms compromising response to single anti-cancer targeted therapies. The implementation of combinatorial approaches involving MEK1/2 or KRASG12C inhibitors in the context of KRAS-mutated lung cancers focuses fundamentally on targeting KRAS proximal activators or effectors. However, the antitumor effect is highly determined by compensatory mechanisms arising in defined cell types or tumor subgroups. A potential strategy to find drug combinations targeting a larger fraction of KRAS-mutated lung cancers may capitalize on the common, distal gene expression output elicited by oncogenic KRAS. By integrating a signature-driven drug repurposing approach with a pairwise pharmacological screen, here we show synergistic drug combinations consisting of multi-tyrosine kinase PKC inhibitors together with MEK1/2 or KRASG12C inhibitors. Such combinations elicit a cytotoxic response in both in vitro and in vivo models, which in part involves inhibition of the PKC inhibitor target AURKB. Proteome profiling links dysregulation of MYC expression to the effect of both PKC inhibitor-based drug combinations. Furthermore, MYC overexpression appears as a resistance mechanism to MEK1/2 and KRASG12C inhibitors. Our study provides a rational framework for selecting drugs entering combinatorial strategies and unveils MEK1/2- and KRASG12C-based therapies for lung cancer.