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

Simple item page
dc.contributor.authorMacaya, Irati
dc.contributor.authorRoman, Marta
dc.contributor.authorWelch, Connor
dc.contributor.authorEntrialgo-Cadierno, Rodrigo
dc.contributor.authorSalmon, Marina
dc.contributor.authorSantos, Alba
dc.contributor.authorFeliu, Iker
dc.contributor.authorKovalski, Joanna
dc.contributor.authorLópez Erdozain, Inés
dc.contributor.authorRodríguez-Remírez, María
dc.contributor.authorPalomino Echeverría, Sara
dc.contributor.authorLonfgren, Shane M.
dc.contributor.authorFerrero, Macarena
dc.contributor.authorCalabuig, Silvia
dc.contributor.authorLudwig, Iziar A.
dc.contributor.authorLara-Astiaso, David
dc.contributor.authorJantus-Lewintre, Eloisa
dc.contributor.authorGuruceaga, Elizabeth
dc.contributor.authorNarayanan, Shruthi
dc.contributor.authorPonz Sarvisé, Mariano
dc.contributor.authorPineda Lucena, Antonio
dc.contributor.authorLecanda, Fernando
dc.contributor.authorRuggero, Davide
dc.contributor.authorKhatri, Purvesh
dc.contributor.authorSantamaría Martínez, Enrique
dc.contributor.authorFernández Irigoyen, Joaquín
dc.contributor.authorFerrer, Irene
dc.contributor.authorPaz-Ares, Luis
dc.contributor.authorDrosten, Matthias
dc.contributor.authorBarbacid, Mariano
dc.contributor.authorGil-Bazo, Ignacio
dc.contributor.authorVicent, Silvestre
dc.contributor.departmentCiencias de la Saludes_ES
dc.contributor.departmentOsasun Zientziakeu
dc.date.accessioned2024-04-25T10:03:02Z
dc.date.available2024-04-25T10:03:02Z
dc.date.issued2023
dc.date.updated2024-04-25T09:55:13Z
dc.description.abstractDrug 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.en
dc.description.sponsorshipM.R. was supported by a fellowship from MICIU (FPU15/00173). The Proteomics Platforms of Navarrabiomed led by E.S. and J.F.-I. is a member of Proteored, PRB3 and is supported by grant PT17/0019 of the PE I + D + i 2013¿2016, funded by ISCIII and ERDF. E.J.-L. was supported by Foundation of Spanish Association Against Cancer (PROYE18012ROSE), by Centro de Investigación Biomédica en Red (CIBERONC; CB16-12-00350), and by Generalitat Valenciana (AICO/ 2021/333). F.L. was funded by the Gobierno de Navarra (Ref. 34/2021), the Cancer Research Thematic Network of the Instituto de Salud Carlos III (RTICC RD12/0036/0066), PID2021-122638OB-I00 MCIN/AEI/ 10.13039/501100011033/ FEDER, UE and by FEDER ¿Una manera de hacer Europa¿. I.F. was funded by FIS PI19/00320 and by the Miguel Servet Program CP21/00052. S.V. was supported by Ministerio de Ciencia, Innovación y Universidades, Convocatoria 2019 para incentivar la Incorporación Estable de Doctores (IED2019-001007-I), by FEDER /Ministerio de Ciencia, Innovación y Universidades - Agencia Estatal de Investigación (SAF2017-89944-R and PID2020¿116344¿RB¿100/MCIN/ AEI/10.13039/501100011033, by a Leonardo Grant for Researchers and Cultural Creators 2018 from BBVA Foundation, by a seed grant at the I Convocatoria Proyectos Prueba de Concepto from PRB3-Proteored (Institute of Health Carlos III-ISCIII), by Fundació La Marató de TV3 (474/ C/2019), and by Foundation of Spanish Association Against Cancer - Strategic Projects 2020 (PROYE20029VICE). M.P.-S. and S.V. were also funded by Fundación Alberto Palatchi.en
dc.format.mimetypeapplication/pdfen
dc.identifier.citationMacaya, 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.es_ES
dc.identifier.doi10.1038/s41467-023-41828-z
dc.identifier.issn2041-1723
dc.identifier.urihttps://academica-e.unavarra.es/handle/2454/48035
dc.language.isoengen
dc.publisherSpringer Natureen
dc.relation.ispartofNature Communications (2023), vol. 14, 6332es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/MICINN/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/T17%2F0019/
dc.relation.projectIDinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2021-122638OB-I00/ES/
dc.relation.projectIDinfo:eu-repo/grantAgreement/ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII)/PI19%2F00320/ES/
dc.relation.projectIDinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-89944-R/ES/
dc.relation.projectIDinfo:eu-repo/grantAgreement/MICINN//PID2020‐116344‐RB-I00/
dc.relation.projectIDinfo:eu-repo/grantAgreement/Gobierno de Navarra//34%2F2021/
dc.relation.publisherversionhttps://doi.org/10.1038/s41467-023-41828-z
dc.rights© The Author(s) 2023. This article is licensed under a Creative Commons Attribution 4.0 International License.es_ES
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectMidostaurinen
dc.subjectMEK1/2 inhibitorssen
dc.subjectKRASG12C inhibitorsen
dc.subjectLung canceren
dc.titleSignature-driven repurposing of Midostaurin for combination with MEK1/2 and KRASG12C inhibitors in lung canceren
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/acceptedVersion
dspace.entity.typePublication
relation.isAuthorOfPublication97833b7b-2aa3-43ae-a0e0-fdd4c132c8df
relation.isAuthorOfPublicationabacfd17-2b93-4d99-bae2-52053d57401e
relation.isAuthorOfPublication86d1b76e-4790-40b1-a3ec-72331c5c6199
relation.isAuthorOfPublication.latestForDiscovery97833b7b-2aa3-43ae-a0e0-fdd4c132c8df

Files

Original bundle
Now showing 1 - 2 of 2
Thumbnail Image
Name:
Macaya_SignatureDriven.pdf
Size:
4.39 MB
Format:
Adobe Portable Document Format
Download
Thumbnail Image
Name:
Macaya_SignatureDriven_MATCOMPL.pdf
Size:
10.28 MB
Format:
Adobe Portable Document Format
Download
License bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
1.78 KB
Format:
Item-specific license agreed to upon submission
Description:
Download

Collections

Artículos de revista DCS - OZS Aldizkari artikuluak
Artículos de revista - Aldizkari artikuluak