Abstract 1715: 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 3-5% of non-small cell lung cancers (NSCLC), colorectal cancers (CRC) and melanomas. The recent development of novel SOS1 inhibitors, including BI-3406 and BI-1701963, 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. Of the 11 available SOS1-mutant cancer cell lines without RAS co-mutation, 10 were sensitive to SOS1 inhibition in 2D and/or 3D cell culture, while cells with SOS1 and RAS co-mutations were resistant to SOS1 inhibition. Treatment with a SHP2 inhibitor, which is presumed to inhibit the activity of both SOS1 and SOS2, revealed a subset of SOS1-mutant cell lines that were more sensitive to SHP2 inhibition than SOS1 inhibition. This implied that, in certain settings, SOS2 can compensate for the loss of SOS1 activity. Accordingly, these cells exhibited a rebound in RAS signaling after treatment with SOS1i that was dependent on SOS2. SOS2 knock-down further sensitized these cells to SOS1 inhibition, resulting in responses equivalent to SHP2 inhibition. In addition, we show that, as with SOS1, SOS2 is a target for ERK1/2-dependent feedback phosphorylation. Thus, relief of ERK1/2-dependent negative regulation of SOS2, following SOS1 inhibition, likely contributes to receptor tyrosine kinase (RTK)-SOS2 activation that may mediate SOS1 inhibitor resistance in some contexts. In vivo, SOS1i inhibited tumor growth in xenograft models of SOS1-mutant AML and NSCLC. 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, Regina Ruzicka, Robin Jacob, Christoph Albrecht, Teresa Zanin, Tom Madensky, Kaja Kostyrko, Robyn L. Schenk, Anke Baum, 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 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1715.