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Receptor-interacting protein kinase 2 (RIPK2) stabilizes c-Myc and is a therapeutic target in prostate cancer

Yiwu Yan1, Bo Zhou1,2, Chen Qian1

  • 1Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Nature Communications
|February 4, 2022
PubMed

Insights

Targeting receptor-interacting protein kinase 2 (RIPK2) can inhibit prostate cancer (PC) metastasis. RIPK2 inhibition impacts the c-Myc pathway, reducing metastatic outgrowth and improving survival in lethal metastatic castration-resistant PC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Distant metastasis is a primary driver of mortality in prostate cancer (PC).
  • Developing therapies to prevent or delay PC metastasis is crucial for improving patient outcomes.
  • Receptor-interacting protein kinase 2 (RIPK2) is implicated in PC progression.

Purpose of the Study:

  • To identify and validate RIPK2 as a druggable target for inhibiting PC metastasis.
  • To elucidate the molecular mechanisms by which RIPK2 promotes PC metastasis.
  • To evaluate the efficacy of RIPK2 inhibition in preclinical models of PC metastasis.

Main Methods:

  • Analysis of clinical data correlating RIPK2 amplification/gain with lethal metastatic castration-resistant PC.
  • Genetic knockout of RIPK2 in PC models to assess its role in metastasis.
  • Multi-level proteomics to identify RIPK2-regulated pathways.
  • Investigating the RIPK2 interaction with mitogen-activated protein kinase kinase 7 (MKK7) and its role in c-Myc regulation.
  • Utilizing preclinical and clinical drugs targeting RIPK2.

Main Results:

  • RIPK2 is amplified/gained in approximately 65% of lethal metastatic castration-resistant PC cases.
  • RIPK2 overexpression correlates with disease progression and poor prognosis.
  • Genetic deletion of RIPK2 significantly reduces PC metastasis.
  • RIPK2 activates MKK7, a direct c-Myc-S62 kinase, thereby regulating c-Myc stability and activity.
  • RIPK2 inhibition effectively impairs PC metastatic outgrowth by inactivating the RIPK2/MKK7/c-Myc pathway.

Conclusions:

  • RIPK2 is a clinically actionable target for inhibiting prostate cancer metastasis.
  • Targeting the RIPK2/MKK7/c-Myc signaling axis offers a promising therapeutic strategy.
  • Inhibition of RIPK2 signaling can potentially extend metastasis-free and overall survival in PC patients.

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