{"doi":"10.1101/2020.10.08.331835","title":"Silencing of oncogenic KRAS by mutant-selective small interfering RNA","abstract":"Abstract Oncogenic mutations in the KRAS gene are well-established drivers of cancer. While the recently developed KRAS G12C inhibitors offer a targeted KRAS therapy and have shown success in the clinic, KRAS G12C represents only 11% of all KRAS mutations. Current therapeutic approaches for all other KRAS mutations are both indirect and non-mutant-selective, largely focusing on inhibition of downstream KRAS effectors such as MAP kinases. Inhibition of KRAS downstream signaling results in a system-wide down-modulation of the respective targets, raising concerns about systemic cell toxicity. Here, we describe a custom short interfering RNA (siRNA) oligonucleotide (EFTX-D1) designed to preferentially bind mRNA of the most commonly occurring KRAS missense mutations in codons 12 and 13. We determined that EFTX-D1 preferentially reduced the mutant KRAS sequence versus wild-type at the levels of both transcription and translation, and reversed oncogenic KRAS-induced morphologic and growth transformation. Furthermore, EFTX-D1 significantly impaired the proliferation of several KRAS mutant cancer cell lines in 2-D as well as 3-D assays. Taken together, our data indicate a novel use of RNA interference (RNAi) to target oncogenic KRAS-driven cancers specifically.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":125450,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9479,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":316540,"name":"Salma H. Azam","orcid":"0000-0003-1861-0475","position":1,"is_corresponding":false},{"id":572058,"name":"Anne Y. Feng","orcid":null,"position":2,"is_corresponding":false},{"id":267505,"name":"Amanda E.D. Van Swearingen","orcid":"0000-0002-4287-9741","position":3,"is_corresponding":false},{"id":572059,"name":"Christina Gutierrez-Ford","orcid":null,"position":4,"is_corresponding":false},{"id":436820,"name":"Pradeep S. Pallan","orcid":null,"position":5,"is_corresponding":false},{"id":435753,"name":"Martin Egli","orcid":"0000-0003-4145-356X","position":6,"is_corresponding":false},{"id":449324,"name":"Adrienne D. Cox","orcid":"0000-0002-4901-2454","position":7,"is_corresponding":false},{"id":254947,"name":"Channing J. Der","orcid":"0000-0002-7751-2747","position":8,"is_corresponding":false},{"id":316543,"name":"Chad V. Pecot","orcid":"0000-0002-5250-2999","position":9,"is_corresponding":false},{"id":571507,"name":"Bjoern Papke","orcid":"0000-0001-8156-7508","position":0,"is_corresponding":true}],"reference_count":35,"raw_metadata":null,"created_at":"2026-07-18T23:15:15.482227Z","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":[]}