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
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<sup>KO</sup> 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<sup>mut</sup> 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<sup>mut</sup> allografts assays in immunocompromised mice, our analyses using an in vivo model of KRAS<sup>G12D</sup>-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<sup>G12D</sup> 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.
Authors
- Nuria Calzada (ORCID: https://orcid.org/0000-0003-4536-8581)
- Chiara Ambrogio (ORCID: https://orcid.org/0000-0003-4122-701X)
- Rósula García‐Navas (ORCID: https://orcid.org/0000-0002-8956-3904)
- Esther Castellano (ORCID: https://orcid.org/0000-0002-8449-4081)
- Javier Borrajo-Sánchez (ORCID: https://orcid.org/0000-0001-6418-7845)
- Heribert Arnhof
- Marco H. Hofmann (ORCID: https://orcid.org/0000-0001-7557-1156)
- Fernando C. Baltanás (ORCID: https://orcid.org/0000-0001-8110-0991)
- Andrea Olarte-San Juan (ORCID: https://orcid.org/0000-0002-3793-3205)
- Maximilian Kramer‐Drauberg (ORCID: https://orcid.org/0000-0001-8122-3107)
- Kaja Kostyrko (ORCID: https://orcid.org/0000-0002-2842-4089)
- Barbara Mair (ORCID: https://orcid.org/0000-0001-6982-2529)
- Eugenio Santos (ORCID: https://orcid.org/0000-0003-3565-0321)
- Enrico Patrucco (ORCID: https://orcid.org/0000-0001-8060-5058)
- Pablo Rodríguez-Ramos (ORCID: https://orcid.org/0000-0002-3766-1406)
- E. Petrini (ORCID: https://orcid.org/0009-0002-5976-274X)
Institutions
- Consejo Superior de Investigaciones Científicas (ES)
- Universidad de Salamanca (ES)
- Boehringer Ingelheim (Austria) (AT)
- Instituto de Biomedicina de Sevilla (ES)
- Centro de Investigación del Cáncer (ES)
- Hospital Universitario Virgen del Rocío (ES)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- University of Turin (IT)
- Universidad de Sevilla (ES)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-03-12
- DOI
- https://doi.org/10.1073/pnas.2422943122
- Citations
- 8
- Primary Topic
- Protein Kinase Regulation and GTPase Signaling
- Type
- article
- Field-Weighted Citation Impact
- 6.45
Funders
- Giovanni Armenise-Harvard Foundation
- Fundación Científica Asociación Española Contra el Cáncer
- Fondazione Umberto Veronesi
- Ministerio de Ciencia e Innovación
- Junta de Castilla y León
- Instituto de Salud Carlos III
- HORIZON EUROPE European Research Council