Ectopic JAK-STAT activation enables the transition to a stem-like and multilineage state conferring AR-targeted therapy resistance.

Autor: Deng S; Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA., Wang C; Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA., Wang Y; Quantitative Biomedical Research Center, Department of Population and Data Sciences, UT Southwestern Medical Center, Dallas, TX, USA., Xu Y; Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA., Li X; Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA., Johnson NA; Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA., Mukherji A; Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA., Lo UG; Department of Urology, UT Southwestern Medical Center, Dallas, TX, USA., Xu L; Department of Pathology, Duke University School of Medicine, Durham, NC, USA., Gonzalez J; Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA., Metang LA; Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA., Ye J; Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX, USA., Tirado CR; Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA., Rodarte K; Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX, USA., Zhou Y; Department of Pathology, Duke University School of Medicine, Durham, NC, USA., Xie Z; Quantitative Biomedical Research Center, Department of Population and Data Sciences, UT Southwestern Medical Center, Dallas, TX, USA., Arana C; Wakeland Genomics Core, UT Southwestern Medical Center, Dallas, TX, USA., Annamalai V; Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA., Liu X; Department of Urology, UT Southwestern Medical Center, Dallas, TX, USA., Vander Griend DJ; Department of Pathology, The University of Illinois at Chicago, Chicago, IL, USA., Strand D; Department of Urology, UT Southwestern Medical Center, Dallas, TX, USA., Hsieh JT; Department of Urology, UT Southwestern Medical Center, Dallas, TX, USA., Li B; Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX, USA., Raj G; Department of Urology, UT Southwestern Medical Center, Dallas, TX, USA., Wang T; Quantitative Biomedical Research Center, Department of Population and Data Sciences, UT Southwestern Medical Center, Dallas, TX, USA., Mu P; Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA. ping.mu@utsouthwestern.edu.; Hamon Center for Regenerative Science and Medicine, UT Southwestern Medical Center, Dallas, TX, USA. ping.mu@utsouthwestern.edu.; Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA. ping.mu@utsouthwestern.edu.
Jazyk: angličtina
Zdroj: Nature cancer [Nat Cancer] 2022 Sep; Vol. 3 (9), pp. 1071-1087. Date of Electronic Publication: 2022 Sep 05.
DOI: 10.1038/s43018-022-00431-9
Abstrakt: Emerging evidence indicates that various cancers can gain resistance to targeted therapies by acquiring lineage plasticity. Although various genomic and transcriptomic aberrations correlate with lineage plasticity, the molecular mechanisms enabling the acquisition of lineage plasticity have not been fully elucidated. We reveal that Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling is a crucial executor in promoting lineage plasticity-driven androgen receptor (AR)-targeted therapy resistance in prostate cancer. Importantly, ectopic JAK-STAT activation is specifically required for the resistance of stem-like subclones expressing multilineage transcriptional programs but not subclones exclusively expressing the neuroendocrine-like lineage program. Both genetic and pharmaceutical inhibition of JAK-STAT signaling resensitizes resistant tumors to AR-targeted therapy. Together, these results suggest that JAK-STAT are compelling therapeutic targets for overcoming lineage plasticity-driven AR-targeted therapy resistance.
(© 2022. The Author(s).)
Databáze: MEDLINE
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