{"doi":"10.1101/2023.01.20.524989","title":"SOS2 regulates the threshold of mutant <i>EGFR</i> -dependent oncogenesis","abstract":"Abstract Son of Sevenless 1 and 2 (SOS1 and SOS2) are RAS guanine nucleotide exchange factors (RasGEFs) that mediate physiologic and pathologic RTK-dependent RAS activation. Here, we show that SOS2 modulates the threshold of epidermal growth factor receptor (EGFR) signaling to regulate the efficacy of and resistance to the EGFR-TKI osimertinib in lung adenocarcinoma (LUAD). SOS2 deletion sensitized EGFR -mutated cells to perturbations in EGFR signaling caused by reduced serum and/or osimertinib treatment to inhibit PI3K/AKT pathway activation, oncogenic transformation, and survival. Bypass RTK reactivation of PI3K/AKT signaling represents a common resistance mechanism to EGFR-TKIs; SOS2 KO reduced PI3K/AKT reactivation to limit osimertinib resistance. In a forced HGF/MET-driven bypass model, SOS2 KO inhibited HGF-stimulated PI3K signaling to block HGF-driven osimertinib resistance. Using a long term in situ resistance assay, a majority of osimertinib resistant cultures exhibited a hybrid epithelial/mesenchymal phenotype associated with reactivated RTK/AKT signaling. In contrast, RTK/AKT-dependent osimertinib resistance was markedly reduced by SOS2 deletion; the few SOS2 KO cultures that became osimertinib resistant primarily underwent non-RTK dependent EMT. Since bypass RTK reactivation and/or tertiary EGFR mutations represent the majority of osimertinib-resistant cancers, these data suggest that targeting SOS2 has the potential to eliminate the majority of osimertinib resistance. One sentence summary SOS2 modulates the threshold of EGFR-PI3K signaling to regulate the efficacy of and resistance to osimertinib.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":394058,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9543,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":865621,"name":"Amanda J. Linke","orcid":"0000-0001-5719-9696","position":1,"is_corresponding":false},{"id":902073,"name":"Nancy E. Sealover","orcid":"0000-0002-6463-5836","position":2,"is_corresponding":false},{"id":991260,"name":"Brianna R. Daley","orcid":"0009-0008-3018-9963","position":3,"is_corresponding":false},{"id":1081737,"name":"Johnny Yang","orcid":"0000-0003-2690-3155","position":4,"is_corresponding":false},{"id":924006,"name":"Katherine Cox","orcid":"0000-0003-0974-8341","position":5,"is_corresponding":false},{"id":902079,"name":"Robert L. Kortum","orcid":"0000-0002-1634-4882","position":6,"is_corresponding":false},{"id":1078016,"name":"Patricia L. Theard","orcid":"0000-0001-9761-7645","position":0,"is_corresponding":true}],"reference_count":76,"raw_metadata":null,"created_at":"2026-07-19T01:19:10.334330Z","pmid":"37425733","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}