Protein Kinase Regulation and GTPase Signaling
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Responses to KRASG12C plus SOS1i to be a promising strategy for treating both KRASG12Ci naive and relapsed KRASG12C-mutant tumors.
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Combination approaches are needed to strengthen and extend the clinical response to KRASG12C inhibitors (KRASG12Ci). Here, we assessed the antitumor responses of KRASG12C mutant lung and colorectal cancer models to combination treatment with a SOS1 inhibitor (SOS1i), BI-3406, plus the KRASG12C 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 KRASG12Ci 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 KRASG12Ci treatment. These results suggest KRASG12C plus SOS1i to be a promising strategy for treating both KRASG12Ci naive and relapsed KRASG12C-mutant tumors.
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@article{Thatikonda2024targeting,
title = {Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance},
author = {Venu Thatikonda and Hengyu Lyu and Sabine Jurado and Kaja Kostyrko and Christopher A. Bristow and Christoph Albrecht and Donát Alpár and Heribert Arnhof and Oliver Bergner and Karin Bosch and Ningping Feng and Sisi Gao and Daniel Gerlach and Michael Gmachl and Melanie Hinkel and Simone Lieb and Astrid Jeschko and Annette A. Machado and Thomas Madensky and Ethan D. Marszalek and Mikhila Mahendra and Gabriella Melo‐Zainzinger and Jessica M. Molkentine and Philipp A. Jaeger and David H. Peng and Robyn L. Schenk and Alexey V. Sorokin and Sandra J. Strauss and Francesca Trapani and Scott Kopetz and Christopher P. Vellano and Mark Petronczki and Norbert Kraut and Timothy P. Heffernan and Joseph R. Marszalek and Mark Pearson and Irene C. Waizenegger and Marco H. Hofmann},
journal = {Nature Cancer},
year = {2024},
doi = {10.1038/s43018-024-00800-6},
url = {https://doi.org/10.1038/s43018-024-00800-6}
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