{"doi":"10.1016/j.tranon.2020.100913","title":"Enhanced efficacy of JAK1 inhibitor with mTORC1/C2 targeting in smoldering/chronic adult T cell leukemia","abstract":"Adult T-cell leukemia (ATL) is an aggressive T-cell lymphoproliferative malignancy of regulatory T lymphocytes (Tregs), caused by human T-cell lymphotropic virus 1 (HTLV-1). Interleukin 2 receptor alpha (IL-2Rα) is expressed in the leukemic cells of smoldering/chronic ATL patients, leading to constitutive activation of the JAK/STAT pathway and spontaneous proliferation. The PI3K/AKT/mTOR pathway also plays a critical role in ATL cell survival and proliferation. We previously performed a high-throughput screen that demonstrated additive/synergistic activity of Ruxolitinib, a JAK1/2 inhibitor, with AZD8055, an mTORC1/C2 inhibitor. However, effects of unintended JAK2 inhibition with Ruxolitinib limits it therapeutic potential for ATL patients, which lead us to evaluate a JAK1-specific inhibitor. Here, we demonstrated that Upadacitinib, a JAK-1 inhibitor, inhibited the proliferation of cytokine-dependent ATL cell lines and the expression of p-STAT5. Combinations of Upadacitinib with either AZD8055 or Sapanisertib, mTORC1/C2 inhibitors, showed anti-proliferative effects against cytokine-dependent ATL cell lines and synergistic effect with reducing tumor growth in NSG mice bearing IL-2 transgenic tumors. Importantly, the combination of these two agents inhibited ex vivo spontaneous proliferation of ATL cells from patients with smoldering/chronic ATL. Combined targeting of JAK/STAT and PI3K/AKT/mTOR pathways represents a promising therapeutic intervention for patients with smoldering/chronic ATL.","journal":"Translational Oncology","year":2020,"id":82300,"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":13,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9541,"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":424596,"name":"Yuquan Lin","orcid":"0009-0003-2047-1563","position":1,"is_corresponding":false},{"id":392223,"name":"Meili Zhang","orcid":"0000-0002-6970-6154","position":2,"is_corresponding":false},{"id":425440,"name":"Bonita R. Bryant","orcid":null,"position":3,"is_corresponding":false},{"id":408245,"name":"Michael Petrus","orcid":null,"position":4,"is_corresponding":false},{"id":425441,"name":"Richard N. Bamford","orcid":null,"position":5,"is_corresponding":false},{"id":258191,"name":"Craig J. Thomas","orcid":"0000-0001-9386-9001","position":6,"is_corresponding":false},{"id":238494,"name":"Miloš D. Miljković","orcid":"0000-0001-5848-6320","position":7,"is_corresponding":false},{"id":238495,"name":"Kevin C. Conlon","orcid":"0000-0002-4118-7524","position":8,"is_corresponding":false},{"id":238492,"name":"Thomas A. Waldmann","orcid":"0000-0003-4500-6660","position":9,"is_corresponding":false},{"id":424595,"name":"Anusara Daenthanasanmak","orcid":"0000-0002-6404-7444","position":0,"is_corresponding":true}],"reference_count":39,"raw_metadata":null,"created_at":"2026-07-18T21:53:19.932222Z","pmid":"33129109","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":[]}