{"doi":"10.1111/cas.15364","title":"Targeting chemoresistance in Xp11.2 translocation renal cell carcinoma using a novel polyamide–chlorambucil conjugate","abstract":"Renal cell carcinoma with Xp11.2 translocation involving the TFE3 gene (TFE3-RCC) is a recently identified subset of RCC with unique morphology and clinical presentation. The chimeric PRCC-TFE3 protein produced by Xp11.2 translocation has been shown to transcriptionally activate its downstream target genes that play important roles in carcinogenesis and tumor development of TFE3-RCC. However, the underlying molecular mechanisms remain poorly understood. Here we show that in TFE3-RCC cells, PRCC-TFE3 controls heme oxygenase 1 (HMOX1) expression to confer chemoresistance. Inhibition of HMOX1 sensitized the PRCC-TFE3 expressing cells to genotoxic reagents. We screened for a novel chlorambucil-polyamide conjugate (Chb) to target PRCC-TFE3-dependent transcription, and identified Chb16 as a PRCC-TFE3-dependent transcriptional inhibitor of HMOX1 expression. Treatment of the patient-derived cancer cells with Chb16 exhibited senescence and growth arrest, and increased sensitivity of the TFE3-RCC cells to the genotoxic reagent etoposide. Thus, our data showed that the TFE3-RCC cells acquired chemoresistance through HMOX1 expression and that inhibition of HMOX1 by Chb16 may be an effective therapeutic strategy for TFE3-RCC.","journal":"Cancer Science","year":2022,"id":288746,"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":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9484,"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":969487,"name":"Sally Mehanna","orcid":"0000-0002-4193-0058","position":1,"is_corresponding":false},{"id":969488,"name":"Wenjuan Ma","orcid":"0009-0004-3642-0493","position":2,"is_corresponding":false},{"id":969489,"name":"Hidekazu Nishizawa","orcid":"0000-0001-9315-6650","position":3,"is_corresponding":false},{"id":969490,"name":"Yasuhiko Kamikubo","orcid":"0000-0003-2761-8508","position":4,"is_corresponding":false},{"id":559577,"name":"Hiroshi Sugiyama","orcid":"0000-0001-8923-5946","position":5,"is_corresponding":false},{"id":969491,"name":"Shuji Ikeda","orcid":"0000-0001-7643-5578","position":6,"is_corresponding":false},{"id":969492,"name":"Takanobu Motoshima","orcid":"0000-0001-8774-5803","position":7,"is_corresponding":false},{"id":969493,"name":"Hisashi Hasumi","orcid":"0000-0001-8211-8835","position":8,"is_corresponding":false},{"id":51073,"name":"W. Marston Linehan","orcid":"0000-0001-7983-3109","position":9,"is_corresponding":false},{"id":921011,"name":"Laura S. Schmidt","orcid":"0000-0001-8526-5662","position":10,"is_corresponding":false},{"id":969894,"name":"Chris Ricketts","orcid":null,"position":11,"is_corresponding":false},{"id":504909,"name":"Toshio Suda","orcid":"0000-0001-7540-1771","position":12,"is_corresponding":false},{"id":644860,"name":"Yuichi Oike","orcid":"0000-0003-3245-5395","position":13,"is_corresponding":false},{"id":969494,"name":"Tomomi Kamba","orcid":"0000-0002-5255-6479","position":14,"is_corresponding":false},{"id":504903,"name":"Masaya Baba","orcid":"0000-0002-5308-6683","position":15,"is_corresponding":false},{"id":969893,"name":"Shintaro Funasaki","orcid":null,"position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":null,"created_at":"2026-07-19T00:30:14.968626Z","pmid":"35396773","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":[]}