Scientific publications

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

Oct 10, 2023 | Magazine: Nature Communications

Irati Macaya #  1 , Marta Roman #  1   2 , Connor Welch  1 , Rodrigo Entrialgo-Cadierno  1 , Marina Salmon  3   4 , Alba Santos  4   5 , Iker Feliu  1 , Joanna Kovalski  6   7 , Ines Lopez  1 , Maria Rodriguez-Remirez  1 , Sara Palomino-Echeverria  8 , Shane M Lonfgren  9   10 , Macarena Ferrero  4   11   12 , Silvia Calabuig  4   11   12   13 , Iziar A Ludwig  14 , David Lara-Astiaso  15 , Eloisa Jantus-Lewintre  4   11   12   13 , Elizabeth Guruceaga  16   17   18 , Shruthi Narayanan  1   19 , Mariano Ponz-Sarvise  1   17   19 , Antonio Pineda-Lucena  14 , Fernando Lecanda  1   4   17   20 , Davide Ruggero  6   7   21 , Purvesh Khatri  7   8 , Enrique Santamaria  17   18 , Joaquin Fernandez-Irigoyen  17   18 , Irene Ferrer  4   5 , Luis Paz-Ares  4   5   22   23 , Matthias Drosten  3   24 , Mariano Barbacid  3   4 , Ignacio Gil-Bazo  1   4   17   19   25 , Silve Vicent  26   27   28   29


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.

CITATION  Nat Commun. 2023 Oct 10;14(1):6332.  doi: 10.1038/s41467-023-41828-z

Our authors

Dr. Irati Macaya Erro
Laboratory technician Solid Tumor Research Program
Connor Welch
Rodrigo Entrialgo Cadierno
Elizabet Guruceaga Martínez
Bioinformatics Research Technician Bioinformatics Platform
Shruti Narayanan