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Mutant PIK3CA controls DUSP1-dependent ERK 1/2 activity to confer response to AKT target therapy

A Sathe1, F Guerth1, M V Cronauer2

  • 1Department of Urology, Klinikum rechts der Isar, Technische Universität München, Ismaninger Strasse 22, Munich 81675, Germany.

British Journal of Cancer
|October 29, 2014
PubMed
Abstract

Insights

PIK3CA mutations predict sensitivity to AKT inhibitor MK-2206 in urothelial bladder cancer (BLCA). This sensitivity is mediated by increased DUSP1, leading to ERK1/2 dephosphorylation, apoptosis, and reduced tumor proliferation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • The phosphoinositide 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway is frequently altered in urothelial bladder cancer (BLCA).
  • Targeting the PI3K/AKT/mTOR pathway presents a potential therapeutic strategy for BLCA.
  • The AKT inhibitor MK-2206 was investigated for its efficacy in BLCA.

Purpose of the Study:

  • To evaluate the efficacy of the AKT inhibitor MK-2206 in urothelial bladder cancer (BLCA).
  • To identify molecular determinants that predict response to AKT inhibition therapy in BLCA.

Main Methods:

  • Analysis of biochemical and functional effects of MK-2206 on 11 BLCA cell lines.
  • Assessment of cell viability, apoptosis, and cell cycle progression.
  • Manipulation of PIK3CA, DUSP1, and CREB expression via cDNA or siRNA transfection.
  • In vivo studies using the chicken chorioallantoic membrane model.

Main Results:

  • MK-2206 treatment suppressed AKT and S6K1 phosphorylation in all tested cell lines.
  • Sensitivity to MK-2206 was observed exclusively in cell lines with PIK3CA mutations in the hotspot helical domain.
  • PIK3CA mutations led to increased DUSP1 expression, decreased ERK1/2 phosphorylation, apoptosis, and inhibited tumor proliferation.
  • These effects were confirmed in vitro and in vivo, sensitizing cells to AKT-targeted therapy.

Conclusions:

  • PIK3CA mutations are key determinants of sensitivity to AKT-targeted therapy in BLCA.
  • The mechanism involves DUSP1 upregulation, leading to ERK1/2 dephosphorylation and subsequent cell death and proliferation inhibition.
  • Mutations in PIK3CA can serve as a predictive biomarker for stratifying patients for AKT inhibitor treatment.

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