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Updated: Aug 29, 2025

Time-resolved Förster Resonance Energy Transfer Assays for Measurement of Endogenous Phosphorylated STAT Proteins in Human Cells
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Ectopic JAK-STAT activation enables the transition to a stem-like and multilineage state conferring AR-targeted

Su Deng1, Choushi Wang1, Yunguan Wang2

  • 1Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA.

Nature Cancer
|September 6, 2022
PubMed

Insights

Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling drives resistance to androgen receptor (AR)-targeted therapy in prostate cancer by promoting lineage plasticity. Inhibiting JAK-STAT signaling resensitizes tumors, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Cancer cells can develop resistance to targeted therapies through lineage plasticity.
  • The molecular mechanisms underlying lineage plasticity and therapy resistance are not fully understood.
  • Prostate cancer often develops resistance to androgen receptor (AR)-targeted therapies.

Purpose of the Study:

  • To investigate the role of Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling in driving AR-targeted therapy resistance in prostate cancer.
  • To elucidate the molecular mechanisms by which JAK-STAT signaling contributes to lineage plasticity-driven resistance.
  • To evaluate the therapeutic potential of targeting JAK-STAT signaling to overcome resistance.

Main Methods:

  • Analysis of genomic and transcriptomic data from resistant prostate cancer models.
  • Investigating the requirement of JAK-STAT activation in different resistant subclones.
  • Utilizing genetic and pharmaceutical inhibition of JAK-STAT signaling.
  • Assessing the resensitization of resistant tumors to AR-targeted therapy.

Main Results:

  • Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling is essential for promoting lineage plasticity-driven resistance to AR-targeted therapy in prostate cancer.
  • Ectopic JAK-STAT activation is specifically required for resistance in stem-like subclones with multilineage transcriptional programs, but not in neuroendocrine-like subclones.
  • Both genetic and pharmaceutical inhibition of JAK-STAT signaling effectively resensitized resistant tumors to AR-targeted therapy.

Conclusions:

  • JAK-STAT signaling is a critical mediator of lineage plasticity that confers resistance to AR-targeted therapy in prostate cancer.
  • Targeting JAK-STAT signaling represents a promising therapeutic strategy to overcome acquired resistance in prostate cancer.
  • Further investigation into JAK-STAT pathways could reveal novel approaches for combination therapies.

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