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

Date

2023

Authors

Macaya, Irati
Roman, Marta
Welch, Connor
Entrialgo-Cadierno, Rodrigo
Salmon, Marina
Santos, Alba
Feliu, Iker
Kovalski, Joanna
López Erdozain, Inés
Rodríguez-Remírez, María

Director

Publisher

Springer Nature
Acceso abierto / Sarbide irekia
Artículo / Artikulua
Versión aceptada / Onetsi den bertsioa

Project identifier

  • MICINN/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/T17%2F0019/
  • AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2021-122638OB-I00/ES/ recolecta
  • ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII)/PI19%2F00320/ES/ recolecta
  • AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-89944-R/ES/ recolecta
  • MICINN//PID2020‐116344‐RB-I00/
  • Gobierno de Navarra//34%2F2021/
Impacto
No disponible en Scopus

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.

Description

Keywords

Midostaurin, MEK1/2 inhibitorss, KRASG12C inhibitors, Lung cancer

Department

Ciencias de la Salud / Osasun Zientziak

Faculty/School

Degree

Doctorate program

item.page.cita

Macaya, I., Roman, M., Welch, C., Entrialgo-Cadierno, R., Salmon, M., Santos, A., Feliu, I., Kovalski, J., Lopez, I., Rodriguez-Remirez, M., Palomino-Echeverria, S., Lonfgren, S. M., Ferrero, M., Calabuig, S., Ludwig, I. A., Lara-Astiaso, D., Jantus-Lewintre, E., Guruceaga, E., Narayanan, S., Ponz-Sarvise, M., Pineda-Lucena, A., Lecanda, F., Ruggero, D., Khatri, P., Santamaria, E., Fernandez-Irigoyen, J., Ferrer, I., Paz-Ares, L., Drosten, M., Barbacid, M., Gil-Bazo, I., Vicent, S. (2023) Signature-driven repurposing of Midostaurin for combination with MEK1/2 and KRASG12C inhibitors in lung cancer. Nature Communications, 14(1), 1-19. https://doi.org/10.1038/s41467-023-41828-z.

item.page.rights

© The Author(s) 2023. This article is licensed under a Creative Commons Attribution 4.0 International License.

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