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KDM4B-regulated unfolded protein response as a therapeutic vulnerability in PTEN-deficient breast cancer

Wenyu Wang1, Gokce Oguz1,2, Puay Leng Lee1

  • 1Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Agency for Science, Technology and Research, Biopolis, Singapore.

The Journal of Experimental Medicine
|September 30, 2018
PubMed

Insights

PTEN deficiency in breast cancer causes resistance to PI3K-AKT inhibitors. Targeting KDM4B activates the unfolded protein response (UPR), inducing apoptosis in PTEN-deficient triple-negative breast cancers (TNBCs).

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • PTEN deficiency in breast cancer confers resistance to PI3K-AKT inhibitors.
  • Aberrant activation of the PI3K-AKT signaling pathway is common in PTEN-deficient cancers.

Purpose of the Study:

  • To investigate the role of KDM4B in PTEN-deficient triple-negative breast cancers (TNBCs).
  • To explore KDM4B as a potential therapeutic target for overcoming resistance to PI3K-AKT inhibitors.

Main Methods:

  • Genetic depletion and small molecule inhibition of KDM4B.
  • Assessment of unfolded protein response (UPR) pathway activation.
  • Analysis of apoptosis induction in TNBC cells.
  • Investigation of KDM4B's cytoplasmic interaction with eIF2α.

Main Results:

  • KDM4B inhibition or depletion activates the UPR pathway.
  • This activation leads to preferential apoptosis in PTEN-deficient TNBCs.
  • KDM4B's effect on UPR is independent of its histone demethylase activity and involves cytoplasmic interaction with eIF2α.
  • Combined targeting of KDM4B and PI3K synergistically enhances apoptosis via UPR activation.

Conclusions:

  • KDM4B is a therapeutic vulnerability in PTEN-deficient TNBC.
  • Targeting KDM4B offers a strategy to overcome resistance to PI3K inhibitors in TNBC.
  • KDM4B inhibition induces apoptosis through UPR activation in a PTEN-deficient context.

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