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Tackling Resistance to PI3K Inhibition by Targeting the Epigenome

Shany Koren1, Mohamed Bentires-Alj1

  • 1Department of Biomedicine, University of Basel, University Hospital Basel, 4031 Basel, Switzerland.

Cancer Cell
|May 10, 2017
PubMed

Insights

The epigenetic regulator KMT2D boosts estrogen receptor activity in PIK3CA-mutant breast cancer treated with PI3K inhibitors. Targeting both the epigenome and PI3K signaling may overcome treatment resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Estrogen receptor-positive (ERα) breast cancer is a major health concern.
  • Phosphoinositide-3-kinase (PI3K) pathway inhibitors show promise for ERα-positive breast cancers.
  • Therapeutic resistance to PI3K inhibitors limits clinical efficacy.

Purpose of the Study:

  • To investigate the role of epigenetic regulators in mediating resistance to PI3K inhibitors in breast cancer.
  • To explore the interplay between the KMT2D epigenetic regulator and ERα activity.
  • To identify novel therapeutic strategies by combining epigenome and PI3K pathway targeting.

Main Methods:

  • Utilized PIK3CA-mutant breast cancer models.
  • Administered BYL719 (a PI3K inhibitor).
  • Assessed the impact of KMT2D on ERα activity and cancer cell response.

Main Results:

  • The epigenetic regulator KMT2D was found to enhance ERα activity.
  • This enhancement occurred in the context of PIK3CA-mutant breast cancer treated with BYL719.
  • KMT2D activity contributes to resistance mechanisms against PI3K inhibitors.

Conclusions:

  • KMT2D plays a critical role in ERα activity and resistance to PI3K inhibitors.
  • Targeting the epigenome, specifically KMT2D, alongside PI3K signaling presents a potential therapeutic avenue.
  • This dual-targeting strategy may overcome treatment resistance in ERα-positive breast cancer.

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