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Inhibition of Notch pathway arrests PTEN-deficient advanced prostate cancer by triggering p27-driven cellular

Ajinkya Revandkar1,2, Maria Luna Perciato1, Alberto Toso1

  • 1Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), Bellinzona CH 6500, Switzerland.

Nature Communications
|December 13, 2016
PubMed

Insights

PTEN loss activates NOTCH signaling in prostate cancer by upregulating ADAM17. Targeting this pathway with gamma-secretase inhibitors halts tumor growth, offering a new therapeutic strategy for advanced prostate cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • NOTCH signaling activation correlates with advanced prostate cancer and treatment resistance.
  • The precise mechanisms driving NOTCH activation in prostate cancer are not fully understood.
  • Preclinical data on the efficacy of NOTCH inhibitors in prostate cancer is limited.

Purpose of the Study:

  • To elucidate the mechanism of NOTCH activation in prostate cancer.
  • To investigate the therapeutic potential of NOTCH inhibition in preclinical models of prostate cancer.

Main Methods:

  • Utilized prostate conditional inactivation of Pten and Notch1 in mouse models.
  • Conducted preclinical trials in Pten-null prostate conditional mouse models.
  • Administered pharmacological inhibition of gamma-secretase.

Main Results:

  • PTEN loss was found to upregulate ADAM17, leading to NOTCH signaling activation.
  • Pten-deficient prostate tumors demonstrated dependency on NOTCH signaling.
  • Gamma-secretase inhibition induced growth arrest and cellular senescence in Pten-null and Pten/Trp53-null prostate tumors.

Conclusions:

  • A novel pro-tumorigenic network linking PTEN loss, ADAM17, and NOTCH signaling in prostate cancer was identified.
  • These findings support the use of gamma-secretase inhibitors as a therapeutic strategy for advanced prostate cancer.

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