Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance
Combination approaches are needed to strengthen and extend the clinical response to KRAS<sup>G12C</sup> inhibitors (KRAS<sup>G12C</sup>i). Here, we assessed the antitumor responses of KRAS<sup>G12C</sup> mutant lung and colorectal cancer models to combination treatment with a SOS1 inhibitor (SOS1i), BI-3406, plus the KRAS<sup>G12C</sup> inhibitor, adagrasib. We found that responses to BI-3406 plus adagrasib were stronger than to adagrasib alone, comparable to adagrasib with SHP2 (SHP2i) or EGFR inhibitors and correlated with stronger suppression of RAS-MAPK signaling. BI-3406 plus adagrasib treatment also delayed the emergence of acquired resistance and elicited antitumor responses from adagrasib-resistant models. Resistance to KRAS<sup>G12C</sup>i seemed to be driven by upregulation of MRAS activity, which both SOS1i and SHP2i were found to potently inhibit. Knockdown of SHOC2, a MRAS complex partner, partially restored response to KRAS<sup>G12C</sup>i treatment. These results suggest KRAS<sup>G12C</sup> plus SOS1i to be a promising strategy for treating both KRAS<sup>G12C</sup>i naive and relapsed KRAS<sup>G12C</sup>-mutant tumors.
Authors
- Venu Thatikonda
- Simone Lieb
- Daniel Gerlach (ORCID: https://orcid.org/0000-0001-9338-3765)
- Robyn L. Schenk (ORCID: https://orcid.org/0000-0002-5012-850X)
- Scott Kopetz (ORCID: https://orcid.org/0000-0001-9647-3416)
- David H. Peng (ORCID: https://orcid.org/0000-0003-0511-1888)
- Christopher P. Vellano (ORCID: https://orcid.org/0000-0002-6643-0818)
- Christopher A. Bristow (ORCID: https://orcid.org/0009-0009-9266-6849)
- Irene C. Waizenegger (ORCID: https://orcid.org/0000-0002-3911-6970)
- Sisi Gao (ORCID: https://orcid.org/0000-0002-4809-1699)
- Christoph Albrecht
- Oliver Bergner
- Annette A. Machado (ORCID: https://orcid.org/0000-0002-7996-4907)
- Joseph R. Marszalek (ORCID: https://orcid.org/0000-0003-2320-3209)
- Karin Bosch
- Heribert Arnhof
- Marco H. Hofmann (ORCID: https://orcid.org/0000-0001-7557-1156)
- Jessica M. Molkentine (ORCID: https://orcid.org/0000-0002-3757-7167)
- Donát Alpár (ORCID: https://orcid.org/0000-0002-2638-5418)
- Norbert Kraut (ORCID: https://orcid.org/0000-0003-3941-7105)
- Mark Petronczki (ORCID: https://orcid.org/0000-0003-0139-5692)
- Sabine Jurado
- Sandra J. Strauss (ORCID: https://orcid.org/0000-0001-8328-0260)
- Michael Gmachl (ORCID: https://orcid.org/0009-0002-8783-6611)
- Mikhila Mahendra (ORCID: https://orcid.org/0000-0001-6670-6792)
- Alexey V. Sorokin (ORCID: https://orcid.org/0000-0002-9682-8085)
- Hengyu Lyu (ORCID: https://orcid.org/0000-0003-1093-9364)
- Timothy P. Heffernan (ORCID: https://orcid.org/0000-0002-3166-8922)
- Melanie Hinkel
- Ningping Feng (ORCID: https://orcid.org/0000-0003-1917-9648)
- Kaja Kostyrko (ORCID: https://orcid.org/0000-0002-2842-4089)
- Ethan D. Marszalek
- Astrid Jeschko
- Philipp A. Jaeger (ORCID: https://orcid.org/0000-0002-3624-0802)
- Mark Pearson
- Thomas Madensky
- Francesca Trapani (ORCID: https://orcid.org/0000-0002-8548-9065)
- Gabriella Melo‐Zainzinger
Institutions
- The University of Texas MD Anderson Cancer Center (US)
- BioScientia (Poland) (PL)
- Boehringer Ingelheim (Austria) (AT)
Publication Details
- Journal
- Nature Cancer
- Published
- 2024-08-05
- DOI
- https://doi.org/10.1038/s43018-024-00800-6
- Citations
- 38
- Primary Topic
- Protein Kinase Regulation and GTPase Signaling
- Type
- article
- Field-Weighted Citation Impact
- 8.89
Funders
- Amgen
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- GlaxoSmithKline
- Sanofi
- Gilead Sciences
- Array BioPharma
- Genomic Health
- Taiho Pharmaceutical
- Jazz Pharmaceuticals
- Mirati Therapeutics
- Österreichische Forschungsförderungsgesellschaft
- Servier
- Ono Pharmaceutical
- Ipsen
- Genentech
- EMD Serono
- University of Texas MD Anderson Cancer Center
- Foundation Medicine
- Daiichi Sankyo Europe