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Updated: Jul 8, 2025

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ADORA2A-driven proline synthesis triggers epigenetic reprogramming in neuroendocrine prostate and lung cancers

Na Jing1,2, Kai Zhang1, Xinyu Chen1

  • 1State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell Research Center, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, School of Medicine and School of Biomedical Engineering, and.

The Journal of Clinical Investigation
|December 15, 2023
PubMed

Insights

Targeted therapies fail due to cancer cell plasticity. This study identifies ADORA2A as a key driver of neuroendocrine differentiation, offering a new therapeutic target for prostate and lung cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Cancer cell lineage plasticity contributes to therapeutic resistance.
  • Identifying drivers of this plasticity is crucial for developing effective treatments.

Purpose of the Study:

  • To identify novel drug targets that regulate cancer cell lineage plasticity, specifically neuroendocrine differentiation.

Main Methods:

  • Investigated the role of G protein-coupled receptor ADORA2A in cancer cell lineage plasticity.
  • Utilized genetically engineered mouse models and pharmacological blockade of ADORA2A.
  • Analyzed the signaling pathways involved, including proline metabolism and epigenetic modifications.

Main Results:

  • ADORA2A is upregulated during neuroendocrine differentiation in prostate and lung cancers.
  • ADORA2A activation alters proline metabolism via an ERK/MYC/PYCR cascade, promoting neuroendocrine lineage.
  • Ablation of ADORA2A inhibits neuroendocrine cancer progression and prevents phenotypic transitions.
  • Pharmacological inhibition of ADORA2A suppresses neuroendocrine cancer growth.

Conclusions:

  • ADORA2A is a critical regulator of neuroendocrine differentiation and a potential therapeutic target.
  • Targeting ADORA2A may overcome resistance in neuroendocrine prostate and lung cancers by modulating epigenetic reprogramming.
Keywords:
EpigeneticsLung cancerMetabolismOncologyProstate cancer

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