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

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 and Silve Vicent ()
Additional contact information
Irati Macaya: University of Navarra, Center for Applied Medical Research, Program in Solid Tumors
Marta Roman: University of Navarra, Center for Applied Medical Research, Program in Solid Tumors
Connor Welch: University of Navarra, Center for Applied Medical Research, Program in Solid Tumors
Rodrigo Entrialgo-Cadierno: University of Navarra, Center for Applied Medical Research, Program in Solid Tumors
Marina Salmon: Spanish National Cancer Center (CNIO)
Alba Santos: Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)
Iker Feliu: University of Navarra, Center for Applied Medical Research, Program in Solid Tumors
Joanna Kovalski: University of California San Francisco
Ines Lopez: University of Navarra, Center for Applied Medical Research, Program in Solid Tumors
Maria Rodriguez-Remirez: University of Navarra, Center for Applied Medical Research, Program in Solid Tumors
Sara Palomino-Echeverria: Universidad Pública de Navarra
Shane M. Lonfgren: Transplantation and Infection
Macarena Ferrero: Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)
Silvia Calabuig: Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)
Iziar A. Ludwig: University of Navarra, Center for Applied Medical Research, Molecular Therapies Program
David Lara-Astiaso: University of Navarra, Center for Applied Medical Research, Genomics Platform
Eloisa Jantus-Lewintre: Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)
Elizabeth Guruceaga: University of Navarra, Center for Applied Medical Research, Bioinformatics Platform
Shruthi Narayanan: University of Navarra, Center for Applied Medical Research, Program in Solid Tumors
Mariano Ponz-Sarvise: University of Navarra, Center for Applied Medical Research, Program in Solid Tumors
Antonio Pineda-Lucena: University of Navarra, Center for Applied Medical Research, Molecular Therapies Program
Fernando Lecanda: University of Navarra, Center for Applied Medical Research, Program in Solid Tumors
Davide Ruggero: University of California San Francisco
Purvesh Khatri: University of California San Francisco
Enrique Santamaria: IdiSNA, Navarra Institute for Health Research
Joaquin Fernandez-Irigoyen: IdiSNA, Navarra Institute for Health Research
Irene Ferrer: Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)
Luis Paz-Ares: Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)
Matthias Drosten: Spanish National Cancer Center (CNIO)
Mariano Barbacid: Spanish National Cancer Center (CNIO)
Ignacio Gil-Bazo: University of Navarra, Center for Applied Medical Research, Program in Solid Tumors
Silve Vicent: University of Navarra, Center for Applied Medical Research, Program in Solid Tumors

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41828-z

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