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

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

  • Nat Cancer. 2022 Sep;3(9):1071-1087. doi: 10.1038/s43018-022-00431-9.
Su Deng  # 1,  Choushi Wang  # 1,  Yunguan Wang  # 2,  Yaru Xu 1,  Xiaoling Li 1,  Nickolas A Johnson 1,  Atreyi Mukherji 1,  U-Ging Lo 3,  Lingfan Xu 4,  Julisa Gonzalez 1,  Lauren A Metang 1,  Jianfeng Ye 5,  Carla Rodriguez Tirado 1,  Kathia Rodarte 6,  Yinglu Zhou 4,  Zhiqun Xie 2,  Carlos Arana 7,  Valli Annamalai 1,  Xihui Liu 3,  Donald J Vander Griend 8,  Douglas Strand 3,  Jer-Tsong Hsieh 4,  Bo Li 5,  Ganesh Raj 3,  Tao Wang 2,  Ping Mu 9 10 11
Affiliations

Affiliations

  • 1 Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA.
  • 2 Quantitative Biomedical Research Center, Department of Population and Data Sciences, UT Southwestern Medical Center, Dallas, TX, USA.
  • 3 Department of Urology, UT Southwestern Medical Center, Dallas, TX, USA.
  • 4 Department of Pathology, Duke University School of Medicine, Durham, NC, USA.
  • 5 Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX, USA.
  • 6 Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX, USA.
  • 7 Wakeland Genomics Core, UT Southwestern Medical Center, Dallas, TX, USA.
  • 8 Department of Pathology, The University of Illinois at Chicago, Chicago, IL, USA.
  • 9 Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA. ping.mu@utsouthwestern.edu.
  • 10 Hamon Center for Regenerative Science and Medicine, UT Southwestern Medical Center, Dallas, TX, USA. ping.mu@utsouthwestern.edu.
  • 11 Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA. ping.mu@utsouthwestern.edu.
  • # Contributed equally.
PMID: 36065066 DOI: 10.1038/s43018-022-00431-9
Abstract

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.

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