共同靶向 SOS1 通过解决内在和获得性耐药性来增强 KRASG12C 抑制剂的抗肿瘤作用。
Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance.
发表日期：2024 Aug 05
作者：
Venu Thatikonda, Hengyu Lyu, Sabine Jurado, Kaja Kostyrko, Christopher A Bristow, Christoph Albrecht, Donat Alpar, Heribert Arnhof, Oliver Bergner, Karin Bosch, Ningping Feng, Sisi Gao, Daniel Gerlach, Michael Gmachl, Melanie Hinkel, Simone Lieb, Astrid Jeschko, Annette A Machado, Thomas Madensky, Ethan D Marszalek, Mikhila Mahendra, Gabriella Melo-Zainzinger, Jessica M Molkentine, Philipp A Jaeger, David H Peng, Robyn L Schenk, Alexey Sorokin, Sandra Strauss, Francesca Trapani, Scott Kopetz, Christopher P Vellano, Mark Petronczki, Norbert Kraut, Timothy P Heffernan, Joseph R Marszalek, Mark Pearson, Irene C Waizenegger, Marco H Hofmann
来源：
Nature Cancer
摘要：
需要联合方法来加强和扩展对 KRASG12C 抑制剂 (KRASG12Ci) 的临床反应。在这里，我们评估了 KRASG12C 突变肺癌和结直肠癌模型对 SOS1 抑制剂 (SOS1i)、BI-3406 和 KRASG12C 抑制剂阿达格拉西联合治疗的抗肿瘤反应。我们发现，对 BI-3406 加阿达格拉西的反应比单独使用阿达格拉西更强，与阿达格拉西与 SHP2 (SHP2i) 或 EGFR 抑制剂相媲美，并且与更强的 RAS-MAPK 信号抑制相关。 BI-3406 加阿达格拉西治疗还延迟了获得性耐药的出现，并引发了阿达格拉西耐药模型的抗肿瘤反应。对 KRASG12Ci 的耐药性似乎是由 MRAS 活性上调驱动的，而 SOS1i 和 SHP2i 均被发现能有效抑制 MRAS 活性。 MRAS 复合物伙伴 SHOC2 的敲低可部分恢复对 KRASG12Ci 治疗的反应。这些结果表明 KRASG12C 联合 SOS1i 是治疗 KRASG12Ci 初治和复发 KRASG12C 突变肿瘤的一种有前途的策略。© 2024。作者。
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.© 2024. The Author(s).