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

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

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

Affiliations

  • 1 University of Navarra, Center for Applied Medical Research, Program in Solid Tumors, Pamplona, Spain.
  • 2 Division of Hematology and Oncology, University of California San Francisco, San Francisco, CA, USA.
  • 3 Experimental Oncology Group, Molecular Oncology Program, Spanish National Cancer Center (CNIO), Madrid, Spain.
  • 4 Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
  • 5 H12O-CNIO Lung Cancer Clinical Research Unit, Instituto de Investigación Hospital 12 de Octubre & Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
  • 6 Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
  • 7 Department of Urology, University of California San Francisco, San Francisco, CA, USA.
  • 8 Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra, Pamplona, Spain.
  • 9 Stanford Institute for Immunity, Transplantation and Infection, Stanford, CA, USA.
  • 10 Stanford Center for Biomedical Informatics Research, Department of Medicine, Stanford University, Stanford, CA, USA.
  • 11 Molecular Oncology Laboratory, Fundación Para La Investigación del Hospital General Universitario de Valencia, Valencia, Spain.
  • 12 Mixed Unit TRIAL (Principe Felipe Research Centre & Fundación para la Investigación del Hospital General Universitario de Valencia), Valencia, Spain.
  • 13 Department of Pathology, Universitat de Valencia, Valencia, Spain.
  • 14 University of Navarra, Center for Applied Medical Research, Molecular Therapies Program, Pamplona, Spain.
  • 15 University of Navarra, Center for Applied Medical Research, Genomics Platform, Pamplona, Spain.
  • 16 University of Navarra, Center for Applied Medical Research, Bioinformatics Platform, Pamplona, Spain.
  • 17 IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
  • 18 ProteoRed-Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
  • 19 Clinica Universidad de Navarra, Department of Medical Oncology, Pamplona, Spain.
  • 20 University of Navarra, Department of Pathology, Anatomy and Physiology, Pamplona, Spain.
  • 21 Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA.
  • 22 Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain.
  • 23 Medical School, Universidad Complutense, Madrid, Spain.
  • 24 Molecular Mechanisms of Cancer Program, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, CSIC-University of Salamanca, Salamanca, Spain.
  • 25 Department of Oncology, Fundación Instituto Valenciano de Oncología, Valencia, Spain.
  • 26 University of Navarra, Center for Applied Medical Research, Program in Solid Tumors, Pamplona, Spain. silvevicent@unav.es.
  • 27 Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain. silvevicent@unav.es.
  • 28 IdiSNA, Navarra Institute for Health Research, Pamplona, Spain. silvevicent@unav.es.
  • 29 University of Navarra, Department of Pathology, Anatomy and Physiology, Pamplona, Spain. silvevicent@unav.es.
  • # Contributed equally.
PMID: 37816716 DOI: 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.

Figures
Products