{"doi":"10.1172/jci177142","title":"Off-target autophagy inhibition by SHP2 allosteric inhibitors contributes to their antitumor activity in RAS-driven cancers","abstract":"Aberrant activation of RAS/MAPK signaling is common in cancer, and efforts to inhibit pathway components have yielded drugs with promising clinical activities. Unfortunately, treatment-provoked adaptive resistance mechanisms inevitably develop, limiting their therapeutic potential. As a central node essential for receptor tyrosine kinase-mediated RAS activation, SHP2 has emerged as an attractive cancer target. Consequently, many SHP2 allosteric inhibitors are now in clinical testing. Here we discovered a previously unrecognized off-target effect associated with SHP2 allosteric inhibitors. We found that these inhibitors accumulate in the lysosome and block autophagic flux in an SHP2-independent manner. We showed that off-target autophagy inhibition by SHP2 allosteric inhibitors contributes to their antitumor activity. We also demonstrated that SHP2 allosteric inhibitors harboring this off-target activity not only suppress oncogenic RAS signaling but also overcome drug resistance such as MAPK rebound and protective autophagy in response to RAS/MAPK pathway blockage. Finally, we exemplified a therapeutic framework that harnesses both the on- and off-target activities of SHP2 allosteric inhibitors for improved treatment of mutant RAS-driven and drug-resistant malignancies such as pancreatic and colorectal cancers.","journal":"Journal of Clinical Investigation","year":2024,"id":433075,"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":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9498,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":662146,"name":"Yunpeng Bai","orcid":"0000-0002-5879-3555","position":1,"is_corresponding":false},{"id":680169,"name":"Jinmin Miao","orcid":"0000-0001-7471-0847","position":2,"is_corresponding":false},{"id":1071943,"name":"Allison A. Murray","orcid":"0000-0002-1586-2813","position":3,"is_corresponding":false},{"id":662143,"name":"Jianping Lin","orcid":"0000-0001-6974-0072","position":4,"is_corresponding":false},{"id":662145,"name":"Jiajun Dong","orcid":"0000-0002-6901-5070","position":5,"is_corresponding":false},{"id":1021288,"name":"Zihan Qu","orcid":"0009-0004-8446-8459","position":6,"is_corresponding":false},{"id":509966,"name":"Ruoyu Zhang","orcid":"0000-0002-4086-9566","position":7,"is_corresponding":false},{"id":1238333,"name":"Quyen Nguyen","orcid":"0000-0002-9726-7566","position":8,"is_corresponding":false},{"id":262043,"name":"Shaomeng Wang","orcid":"0000-0002-8782-6950","position":9,"is_corresponding":false},{"id":924276,"name":"Jingmei Yu","orcid":null,"position":10,"is_corresponding":false},{"id":913467,"name":"Frederick Nguele Meke","orcid":"0000-0001-8542-0343","position":11,"is_corresponding":false},{"id":236994,"name":"Zhong‐Yin Zhang","orcid":"0000-0002-3234-0769","position":12,"is_corresponding":false},{"id":913566,"name":"Yiming Miao","orcid":"0000-0003-0316-5970","position":0,"is_corresponding":true}],"reference_count":83,"raw_metadata":null,"created_at":"2026-07-19T01:59:44.444627Z","pmid":"38842946","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":[]}