Combined KRASG12C and SOS1 inhibition enhances and extends the anti-tumor response in KRASG12C-driven cancers by addressing intrinsic and acquired resistance

Thatikonda, V.; Lu, H.; Jurado, S.; Kostyrko, K.; Bristow, C. A.; Bosch, K.; Feng, N.; Gao, S.; Gerlach, D.; Gerlach, M.; Lieb, S.; Jeschko, A.; Machado, A. A.; Marszalek, E. D.; Mahendra, M.; Jaeger, P. A.; Sorokin, A.; Strauss, S.; Trapani, F.; Kopetz, S.; Vellano, C. P.; Petronczki, M.; Kraut, N.; Heffernan, T. P.; Marszalek, J. R.; Pearson, M.; Waizenegger, I.; Hofmann, M. H.

doi:10.1101/2023.01.23.525210

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bioRxiv · 10.1101/2023.01.23.525210

Combined KRASG12C and SOS1 inhibition enhances and extends the anti-tumor response in KRASG12C-driven cancers by addressing intrinsic and acquired resistance

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Abstract

Efforts to improve the anti-tumor response to KRASG12C targeted therapy have benefited from leveraging combination approaches. Here, we compare the anti-tumor response induced by the SOS1-KRAS interaction inhibitor, BI-3406, combined with a KRASG12C inhibitor (KRASG12Ci) to those induced by KRASG12Ci alone or combined with SHP2 or EGFR inhibitors. In lung cancer and colorectal cancer (CRC) models, BI-3406 plus KRASG12Ci induces an anti-tumor response stronger than that observed with KRASG12Ci alone and comparable to those by the other combinations. This enhanced anti-tumor response is associated with a stronger and extended suppression of RAS-MAPK signaling. Importantly, BI-3406 plus KRASG12Ci treatment delays the emergence of acquired adagrasib resistance in both CRC and lung cancer models and is associated with re-establishment of anti-proliferative activity in KRASG12Ci-resistant CRC models. Our findings position KRASG12C plus SOS1 inhibition therapy as a promising strategy for treating both KRASG12C-mutated tumors as well as for addressing acquired resistance to KRASG12Ci.

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Thatikonda, V., Lu, H., Jurado, S., Kostyrko, K., Bristow, C. A., Bosch, K., Feng, N., Gao, S., Gerlach, D., Gerlach, M., Lieb, S., Jeschko, A., Machado, A. A., Marszalek, E. D., Mahendra, M., Jaeger, P. A., Sorokin, A., Strauss, S., Trapani, F., Kopetz, S., Vellano, C. P., Petronczki, M., Kraut, N., Heffernan, T. P., Marszalek, J. R., Pearson, M., Waizenegger, I., Hofmann, M. H.. 2023-01-23. Combined KRASG12C and SOS1 inhibition enhances and extends the anti-tumor response in KRASG12C-driven cancers by addressing intrinsic and acquired resistance. https://doi.org/10.1101/2023.01.23.525210

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