Abstract 2080: SOS1 inhibition is an effective therapeutic strategy in SOS1-mutant cancer

Abstract SOS1 is a principal guanine nucleotide exchange factor for canonical RAS GTPases and activates RAS signaling. Mutations in SOS1 are found in several prominent cancer types, including 2-4% of NSCLC, CRC, and melanoma. The recent development of novel SOS1 inhibitors (SOS1i), including BI-3406, that block interaction between SOS1 and RAS, presents a potential therapy for SOS1-driven cancers. Here we show that the majority of SOS1 mutations observed in patients enhance RAS guanine nucleotide exchange in cells and activate RAS-MAPK signaling. We treated 11 SOS1 mutant cancer cell lines without RAS co-mutation with a SOS1i and found that 10 were sensitive to SOS1 inhibition in 2D and/or 3D cell culture. In contrast, cell lines with SOS1 and RAS co-mutations were resistant to SOS1 inhibition. In vitro treatment of SOS1 mutant cells with a SHP2 inhibitor, which is presumed to inhibit the activity of both SOS1 and SOS2, revealed a subset of four cell lines that were more sensitive to SHP2 inhibition than SOS1 inhibition. This implied that, in certain contexts, SOS2 can compensate for the loss of SOS1 activity. Accordingly, these cells exhibited a SOS2-dependent rebound in RAS-MAPK signaling after treatment with SOS1i. SOS2 knock-down further sensitized these cells to SOS1 inhibition, resulting in responses equivalent to SHP2 inhibition. Thus, upon SOS1 inhibition relief of ERK1/2-dependent negative regulation likely contributes to receptor tyrosine kinase-driven SOS2 activation that may mediate SOS1 inhibitor resistance in some contexts. In vivo, SOS1i efficiently inhibited tumor growth in four SOS1-mutant NSCLC, CRC, and AML xenograft models. The tumor-suppressive effects of SOS1i in these models were comparable to or stronger than the effects of SHP2i or MEKi. Thus, our results suggest that SOS1 inhibition could be an effective therapeutic approach in RAS wild-type cancer patients with SOS1 mutations. Citation Format: Matthew J. Sale, Neal Mukherjee, Martín Koch, Regina Ruzicka, Robin Jacob, Christoph Albrecht, Teresa Zanin, Thomas Madensky, Robyn L. Schenk, Anke Baum, Kaja Kostyrko, Daniel Gerlach, Marco H. Hofmann, Frank McCormick. SOS1 inhibition is an effective therapeutic strategy in SOS1-mutant cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2080.