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 G12C inhibitors (KRAS G12C i). Here, we assessed the antitumor responses of KRAS G12C mutant lung and colorectal cancer models to combination treatment with a SOS1 inhibitor (SOS1i), BI-3406, plus the KRAS G12C...

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Published in:Nature cancer 2024-09, Vol.5 (9), p.1352-1370
Main Authors: Thatikonda, Venu, Lyu, Hengyu, Jurado, Sabine, Kostyrko, Kaja, Bristow, Christopher A., Albrecht, Christoph, Alpar, Donat, Arnhof, Heribert, Bergner, Oliver, Bosch, Karin, Feng, Ningping, Gao, Sisi, Gerlach, Daniel, Gmachl, Michael, Hinkel, Melanie, Lieb, Simone, Jeschko, Astrid, Machado, Annette A., Madensky, Thomas, Marszalek, Ethan D., Mahendra, Mikhila, Melo-Zainzinger, Gabriella, Molkentine, Jessica M., Jaeger, Philipp A., Peng, David H., Schenk, Robyn L., Sorokin, Alexey, Strauss, Sandra, Trapani, Francesca, Kopetz, Scott, Vellano, Christopher P., Petronczki, Mark, Kraut, Norbert, Heffernan, Timothy P., Marszalek, Joseph R., Pearson, Mark, Waizenegger, Irene C., Hofmann, Marco H.
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container_end_page 1370
container_issue 9
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container_title Nature cancer
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creator Thatikonda, Venu
Lyu, Hengyu
Jurado, Sabine
Kostyrko, Kaja
Bristow, Christopher A.
Albrecht, Christoph
Alpar, Donat
Arnhof, Heribert
Bergner, Oliver
Bosch, Karin
Feng, Ningping
Gao, Sisi
Gerlach, Daniel
Gmachl, Michael
Hinkel, Melanie
Lieb, Simone
Jeschko, Astrid
Machado, Annette A.
Madensky, Thomas
Marszalek, Ethan D.
Mahendra, Mikhila
Melo-Zainzinger, Gabriella
Molkentine, Jessica M.
Jaeger, Philipp A.
Peng, David H.
Schenk, Robyn L.
Sorokin, Alexey
Strauss, Sandra
Trapani, Francesca
Kopetz, Scott
Vellano, Christopher P.
Petronczki, Mark
Kraut, Norbert
Heffernan, Timothy P.
Marszalek, Joseph R.
Pearson, Mark
Waizenegger, Irene C.
Hofmann, Marco H.
description Combination approaches are needed to strengthen and extend the clinical response to KRAS G12C inhibitors (KRAS G12C i). Here, we assessed the antitumor responses of KRAS G12C mutant lung and colorectal cancer models to combination treatment with a SOS1 inhibitor (SOS1i), BI-3406, plus the KRAS G12C 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 G12C 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 G12C i treatment. These results suggest KRAS G12C plus SOS1i to be a promising strategy for treating both KRAS G12C i naive and relapsed KRAS G12C -mutant tumors.
doi_str_mv 10.1038/s43018-024-00800-6
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source Alma/SFX Local Collection
title Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance
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