{"doi":"10.1101/2022.12.06.519395","title":"SOS1 and KSR1 modulate MEK inhibitor responsiveness to target resistant cell populations based on PI3K and KRAS mutation status","abstract":"Abstract KRAS is the most commonly mutated oncogene. Targeted therapies have been developed against mediators of key downstream signaling pathways, predominantly components of the RAF/MEK/ERK kinase cascade. Unfortunately, single-agent efficacy of these agents is limited both by intrinsic and acquired resistance. Survival of drug-tolerant persister cells (DTPs) within the heterogeneous tumor population and/or acquired mutations that reactivate receptor tyrosine kinase (RTK)/RAS signaling can lead to outgrowth of tumor initiating cells (TICs) and drive therapeutic resistance. Here, we show that targeting the key RTK/RAS pathway signaling intermediates SOS1 or KSR1 both enhances the efficacy of, and prevents resistance to, the MEK inhibitor trametinib in KRAS -mutated lung (LUAD) and colorectal (COAD) adenocarcinoma cell lines depending on the specific mutational landscape. The SOS1 inhibitor BI-3406 enhanced the efficacy of trametinib and prevented trametinib resistance by targeting spheroid initiating cells (SICs) in KRAS G12/G13 -mutated LUAD and COAD cell lines that lacked PIK3CA co-mutations. Cell lines with KRAS Q61 and/or PIK3CA mutations were insensitive to trametinib and BI-3406 combination therapy. In contrast, deletion of the RAF/MEK/ERK scaffold protein KSR1 prevented drug-induced SIC upregulation and restored trametinib sensitivity across all tested KRAS mutant cell lines in both PIK3CA - mutated and PIK3CA wildtype cancers. Our findings demonstrate that vertical inhibition of RTK/RAS signaling is an effective strategy to prevent therapeutic resistance in KRAS - mutated cancers, but therapeutic efficacy is dependent on both the specific KRAS mutant and underlying co-mutations. Thus, selection of optimal therapeutic combinations in KRAS -mutated cancers will require a detailed understanding of functional dependencies imposed by allele-specific KRAS mutations. Significance Statement We provide an experimental framework for evaluating both adaptive and acquired resistance to RAS pathway-targeted therapies and demonstrate how targeting specific RAS pathway signaling intermediates SOS1 or KSR1 enhanced effectiveness of and prevented resistance to MEK inhibitors in KRAS -mutated cancer cells with genotypic precision. The contribution of either effector was dependent upon the mutational landscape: SOS1 inhibition synergized with trametinib in KRAS G12/G13 -mutated cells expressing WT PI3K but not in KRAS Q61 -mutated cells or if PIK3CA is mutated. KSR1 deletion inhibited MEK/ERK complex stability and was effective in cells that are unresponsive to SOS1 inhibition. These data demonstrate how a detailed understanding of functional dependencies imposed both by allele specific KRAS mutations and specific co-mutations facilitates the optimization of therapeutic combinations.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":300687,"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":0.9569,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":991261,"name":"Heidi M. Vieira","orcid":"0000-0003-1555-2281","position":1,"is_corresponding":false},{"id":716475,"name":"Chaitra Rao","orcid":"0000-0002-2834-7458","position":2,"is_corresponding":false},{"id":991262,"name":"Jacob M. Hughes","orcid":"0009-0007-6686-5014","position":3,"is_corresponding":false},{"id":991634,"name":"Zaria Beckley","orcid":null,"position":4,"is_corresponding":false},{"id":991263,"name":"Dianna H. Huisman","orcid":"0000-0002-1183-5391","position":5,"is_corresponding":false},{"id":991264,"name":"Deepan Chatterjee","orcid":"0000-0001-7997-7014","position":6,"is_corresponding":false},{"id":902073,"name":"Nancy E. Sealover","orcid":"0000-0002-6463-5836","position":7,"is_corresponding":false},{"id":924006,"name":"Katherine Cox","orcid":"0000-0003-0974-8341","position":8,"is_corresponding":false},{"id":991265,"name":"James W. Askew","orcid":"0000-0002-3110-8976","position":9,"is_corresponding":false},{"id":717289,"name":"Robert A. Svoboda","orcid":null,"position":10,"is_corresponding":false},{"id":566251,"name":"Kurt W. Fisher","orcid":"0000-0002-8391-390X","position":11,"is_corresponding":false},{"id":566250,"name":"Robert E. Lewis","orcid":"0000-0002-3616-2971","position":12,"is_corresponding":false},{"id":902079,"name":"Robert L. Kortum","orcid":"0000-0002-1634-4882","position":13,"is_corresponding":false},{"id":991260,"name":"Brianna R. Daley","orcid":"0009-0008-3018-9963","position":0,"is_corresponding":true}],"reference_count":129,"raw_metadata":null,"created_at":"2026-07-19T00:31:53.559757Z","pmid":null,"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":[]}