{"doi":"10.1007/s00018-024-05280-6","title":"Targeting NG2 relieves the resistance of BRAF-mutant thyroid cancer cells to BRAF inhibitors","abstract":"Abstract BRAF V600E represents a constitutively active onco-kinase and stands as the most prevalent genetic alteration in thyroid cancer. However, the clinical efficacy of small-molecule inhibitors targeting BRAF V600E is often limited by acquired resistance. Here, we find that nerve/glial antigen 2 (NG2), also known as chondroitin sulfate proteoglycan 4 (CSPG4), is up-regulated in thyroid cancers, and its expression is increased with tumor progression in a BRAF V600E -driven thyroid cancer mouse model. Functional studies show that NG2 knockout almost does not affect tumor growth, but significantly improves the response of BRAF-mutant thyroid cancer cells to BRAF inhibitor PLX4720. Mechanistically, the blockade of ERK-dependent feedback by BRAF inhibitor can activate receptor tyrosine kinase (RTK) signaling, causing the resistance to this inhibitor. NG2 knockout attenuates the PLX4720-mediated feedback activation of several RTKs, improving the sensitivity of BRAF-mutant thyroid cancer cells to this inhibitor. Based on this finding, we propose and demonstrate an alternative strategy for targeting NG2 to effectively treat BRAF-mutant thyroid cancers by combining multiple kinase inhibitor (MKI) Sorafenib or Lenvatinib with PLX4720. Thus, this study uncovers a new mechanism in which NG2 contributes to the resistance of BRAF-mutant thyroid cancer cells to BRAF inhibitor, and provides a promising therapeutic option for BRAF-mutant thyroid cancers.","journal":"Cellular and Molecular Life Sciences","year":2024,"id":465597,"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":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9566,"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":1297005,"name":"Guanjie Wang","orcid":"0000-0001-8729-626X","position":1,"is_corresponding":false},{"id":1297006,"name":"Juan Liu","orcid":"0000-0003-2212-8454","position":2,"is_corresponding":false},{"id":1297492,"name":"Mengmeng Yuan","orcid":null,"position":3,"is_corresponding":false},{"id":820804,"name":"Pu Chen","orcid":"0000-0002-6857-2211","position":4,"is_corresponding":false},{"id":371162,"name":"Yao Yao","orcid":"0000-0002-6723-6152","position":5,"is_corresponding":false},{"id":659883,"name":"Shaoqiang Zhang","orcid":"0000-0002-4127-0539","position":6,"is_corresponding":false},{"id":1297007,"name":"Meiju Ji","orcid":"0000-0002-5299-1892","position":7,"is_corresponding":false},{"id":1297008,"name":"Peng Hou","orcid":"0000-0001-7010-7944","position":8,"is_corresponding":false},{"id":1297004,"name":"Fang Sui","orcid":"0000-0002-3167-7730","position":0,"is_corresponding":true}],"reference_count":40,"raw_metadata":null,"created_at":"2026-07-19T02:04:50.328230Z","pmid":"38795180","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":[]}