SOS1 inhibitor BI-3406 shows in vivo antitumor activity akin to genetic ablation and synergizes with a KRAS <sup>G12D</sup> inhibitor in KRAS LUAD
Abstract
We evaluated the in vivo therapeutic efficacy and tolerability of BI-3406-mediated pharmacological inhibition of SOS1 in comparison to genetic ablation of this universal Ras-GEF in various KRAS-dependent experimental tumor settings. Contrary to the rapid lethality caused by SOS1 genetic ablation in SOS2 KO mice, SOS1 pharmacological inhibition by its specific inhibitor BI-3406 did not significantly affect animal weight/viability nor cause noteworthy systemic toxicity. Allograft assays using different KRAS mut cell lines showed that treatment with BI-3406 impaired RAS activation and RAS downstream signaling and decreased tumor burden and disease progression as a result of both tumor-intrinsic and -extrinsic therapeutic effects of the drug. Consistent with prior genetic evidence and the KRAS mut allografts assays in immunocompromised mice, our analyses using an in vivo model of KRAS G12D -driven lung adenocarcinoma (LUAD) in immunocompetent mice showed that single, systemic BI-3406 treatment impaired tumor growth and downmodulated protumorigenic components of the tumor microenvironment comparably to SOS1 genetic ablation or to treatment with the specific KRAS G12D inhibitor MRTX1133. Furthermore, markedly stronger, synergistic antitumor effects were observed upon concomitant treatment with BI-3406 and MRTX1133 in the same in vivo LUAD mouse model. Our data confirm SOS1 as an actionable therapy target in RAS-dependent cancers and suggest that BI-3406 treatment may yield clinical benefit both as monotherapy or as a potential combination partner for multiple RAS-targeting strategies.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (16)
Fernando C. Baltanás
Laboratorio 1. Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas-Universidad de Salamanca and Centro de Investigación Biomédica en Red Cáncer (CIBERONC)
Maximilian Kramer-Drauberg
Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino
Rósula García-Navas
Laboratorio 1. Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas-Universidad de Salamanca and Centro de Investigación Biomédica en Red Cáncer (CIBERONC)
Enrico Patrucco
Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino
Ettore Petrini
Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino
Heribert Arnhof
Boehringer Ingelheim Regional Center Vienna GmbH & Co KG
Andrea Olarte-San Juan
Laboratorio 1. Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas-Universidad de Salamanca and Centro de Investigación Biomédica en Red Cáncer (CIBERONC)
Pablo Rodríguez-Ramos
Laboratorio 1. Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas-Universidad de Salamanca and Centro de Investigación Biomédica en Red Cáncer (CIBERONC)
Javier Borrajo
Departamento de Ciencias Biomédicas y del Diagnóstico, Universidad de Salamanca
Nuria Calzada
Laboratorio 1. Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas-Universidad de Salamanca and Centro de Investigación Biomédica en Red Cáncer (CIBERONC)
Esther Castellano
Laboratorio 5. Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca
Barbara Mair
Boehringer Ingelheim Regional Center Vienna GmbH & Co KG
Kaja Kostyrko
Boehringer Ingelheim Regional Center Vienna GmbH & Co KG
Marco H. Hofmann
Boehringer Ingelheim Regional Center Vienna GmbH & Co KG
Chiara Ambrogio
Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino
Eugenio Santos
Centro de Investigación Biomédica en Red de Cáncer, Instituto de Salud Carlos III