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Neuroendocrine Prostate Cancer Drivers SOX2 and BRN2 Confer Differential Responses to Imipridones ONC201, ONC206, and

Connor Purcell1,2, Praveen R Srinivasan1,3,2, Maximilian Pinho-Schwermann1,3,2

  • 1Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, RI, 02903, USA.

Biorxiv : the Preprint Server for Biology
|September 11, 2024
PubMed

Insights

Neuroendocrine differentiation (NED) in prostate cancer (PCa) does not appear to enhance sensitivity to imipridone drugs. Further studies of imipridones in PCa subtypes are warranted.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Prostate cancer (PCa) is a leading cause of cancer death in men.
  • Neuroendocrine differentiation (NED) confers therapy resistance in approximately 30% of castrate-resistant PCa.
  • Imipridone drugs, including ONC201, show clinical activity in various cancers.

Purpose of the Study:

  • To investigate if NED promotes sensitivity to imipridones ONC201 and ONC206.
  • To explore the role of SOX2 and BRN2 in mediating imipridone sensitivity in PCa.
  • To determine the impact of NED on imipridone efficacy in prostate cancer models.

Main Methods:

  • Inducible overexpression of SOX2 and BRN2 in human PCa cell lines (DU145 and LNCaP).
  • Treatment with imipridones ONC201 and ONC206.
  • Assessment of cell sensitivity and expression of key markers like CLpP.

Main Results:

  • Slight protection from imipridones was observed in LNCaP cells with SOX2/BRN2 overexpression, but not in DU145 cells.
  • SOX2 overexpression in LNCaP cells did not lead to enhanced ONC201 sensitivity, despite increased CLpP expression.
  • DU145 cells overexpressing SOX2 showed significantly reduced sensitivity to ONC201.

Conclusions:

  • NED may not be a significant mechanism of therapy resistance to imipridones in castrate-resistant prostate cancer.
  • Imipridone treatment efficacy may not be substantially affected by NED.
  • Further investigation of imipridones in diverse PCa subtypes is supported.
Keywords:
BRN2, SOX2Neuroendocrine DifferentiationONC201ONC206ONC212Prostate Cancer

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