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The PHLPP2 phosphatase is a druggable driver of prostate cancer progression

Dawid G Nowak1,2, Ksenya Cohen Katsenelson3, Kaitlin E Watrud4

  • 1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY dgn2001@med.cornell.edu.

The Journal of Cell Biology
|May 17, 2019
PubMed

Insights

Complete loss of PHLPP2 blocks prostate cancer growth by destabilizing MYC. This study identifies PHLPP2 as a druggable target for treating PTEN-mutant prostate cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Metastatic prostate cancer frequently involves mutations in PTEN and TP53 tumor suppressor genes.
  • Many candidate tumor suppressors are affected by hemizygous deletions, like the 16q deletion impacting PHLPP2.
  • PHLPP2 is an AKT-suppressing phosphatase implicated in tumor suppressor pathways.

Purpose of the Study:

  • To investigate the role of PHLPP2 in prostate cancer, particularly in the context of Pten/Trp53 mutations.
  • To explore the paradoxical effect of Phlpp2 loss on tumor growth.
  • To identify PHLPP2 as a potential therapeutic target in prostate cancer.

Main Methods:

  • Utilized the RapidCaP genetically engineered mouse model for Pten/Trp53 mutant prostate cancer.
  • Assessed the impact of complete Phlpp2 loss on prostate tumor growth and disease progression.
  • Investigated the interaction between Phlpp2 and Myc, a key driver of prostate cancer.

Main Results:

  • Complete loss of Phlpp2 paradoxically blocked prostate tumor growth and disease progression in the mouse model.
  • Phlpp2 was found to be essential for supporting Myc stability and function.
  • Phlpp2 dephosphorylates threonine-58 of Myc, regulating its stability.
  • Small-molecule inhibitors of PHLPP2 suppressed MYC and induced cell death in PTEN-mutant prostate cancer cells.

Conclusions:

  • Hemizygous deletions of chromosome 16q, involving PHLPP2, represent a druggable vulnerability in prostate cancer.
  • Targeting PHLPP2 phosphatase activity offers a strategy to inhibit MYC protein.
  • PHLPP2 inhibitors show potential for treating PTEN-mutant prostate cancer by targeting MYC.

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