ASCL1 is activated downstream of the ROR2/CREB signaling pathway to support lineage plasticity in prostate cancer

Cell Rep. 2023 Aug 29;42(8):112937. doi: 10.1016/j.celrep.2023.112937. Epub 2023 Aug 7.

Abstract

Lineage plasticity is a form of therapy-induced drug resistance. In prostate cancer, androgen receptor (AR) pathway inhibitors potentially lead to the accretion of tumor relapse with loss of AR signaling and a shift from a luminal state to an alternate program. However, the molecular and signaling mechanisms orchestrating the development of lineage plasticity under the pressure of AR-targeted therapies are not fully understood. Here, a survey of receptor tyrosine kinases (RTKs) identifies ROR2 as the top upregulated RTK following AR pathway inhibition, which feeds into lineage plasticity by promoting stem-cell-like and neuronal networks. Mechanistically, ROR2 activates the ERK/CREB signaling pathway to modulate the expression of the lineage commitment transcription factor ASCL1. Collectively, our findings nominate ROR2 as a potential therapeutic target to reverse the ENZ-induced plastic phenotype and potentially re-sensitize tumors to AR pathway inhibitors.

Keywords: ASCL1; CP: Cancer; CREB; ROR2; cellular plasticity; neuroendocrine; prostate cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgen Receptor Antagonists / therapeutic use
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Line, Tumor
  • Humans
  • Male
  • Neoplasm Recurrence, Local* / drug therapy
  • Prostatic Neoplasms* / genetics
  • Receptor Tyrosine Kinase-like Orphan Receptors / genetics
  • Receptors, Androgen / metabolism
  • Signal Transduction
  • Transcription Factors

Substances

  • Transcription Factors
  • Androgen Receptor Antagonists
  • Receptors, Androgen
  • ASCL1 protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • ROR2 protein, human
  • Receptor Tyrosine Kinase-like Orphan Receptors

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