{"doi":"10.1084/jem.20221563","title":"Genome-wide CRISPR/Cas9 screens reveal shared and cell-specific mechanisms of resistance to SHP2 inhibition","abstract":"SHP2 (PTPN11) acts upstream of SOS1/2 to enable RAS activation. Allosteric SHP2 inhibitors (SHP2i) in the clinic prevent SHP2 activation, block proliferation of RTK- or cycling RAS mutant-driven cancers, and overcome \"adaptive resistance.\" To identify SHP2i resistance mechanisms, we performed genome-wide CRISPR/Cas9 knockout screens on two SHP2i-sensitive cell lines, recovering genes expected to cause resistance (NF1, PTEN, CDKN1B, LZTR1, and RASA2) and novel targets (INPPL1, MAP4K5, epigenetic modifiers). We screened 14 additional lines with a focused CRISPR library targeting common \"hits\" from the genome-wide screens. LZTR1 deletion conferred resistance in 12/14 lines, followed by MAP4K5 (8/14), SPRED2/STK40 (6/14), and INPPL1 (5/14). INPPL1, MAP4K5, or LZTR1 deletion reactivated ERK signaling. INPPL1-mediated sensitization to SHP2i required its NPXY motif but not lipid phosphatase activity. MAP4K5 acted upstream of MEK through a kinase-dependent target(s); LZTR1 had cell-dependent effects on RIT and RAS stability. INPPL1, MAP4K5, or LZTR1 deletion also conferred SHP2i resistance in vivo. Defining the SHP2i resistance landscape could suggest effective combination approaches.","journal":"The Journal of Experimental Medicine","year":2023,"id":326817,"datarank":0.49983067652628066,"base_score":3.332204510175204,"endowment":3.332204510175204,"self_citation_contribution":0.49983067652628066,"citation_network_contribution":0.0,"self_endowment_contribution":0.49983067652628066,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":27,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9521,"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":238057,"name":"Mitchell J. Geer","orcid":"0000-0003-1457-987X","position":1,"is_corresponding":false},{"id":550275,"name":"Xinyi Guo","orcid":"0000-0002-3539-6725","position":2,"is_corresponding":false},{"id":238065,"name":"Igor Dolgalev","orcid":"0000-0003-4451-126X","position":3,"is_corresponding":false},{"id":32220,"name":"Neville E. Sanjana","orcid":"0000-0002-1504-0027","position":4,"is_corresponding":false},{"id":238068,"name":"Benjamin G. Neel","orcid":"0000-0002-9589-585X","position":5,"is_corresponding":false},{"id":1046408,"name":"Wei Wei","orcid":"0000-0001-5556-3941","position":0,"is_corresponding":true}],"reference_count":78,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:08:37.840107Z","pmid":"36820830","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":[]}