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Mechanism of Kemeng Fang's Inhibition of Podocyte Apoptosis in Rats with Membranous Nephropathy through the PI3K/AKT Signaling Pathway
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MEK inhibition leads to PI3K/AKT activation by relieving a negative feedback on ERBB receptors

Alexa B Turke1, Youngchul Song, Carlotta Costa

  • 1Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02129, USA.

Cancer Research
|May 4, 2012
PubMed

Insights

Targeted cancer therapies blocking MEK signaling can paradoxically activate PI3K/AKT pathways in certain cancers. This feedback loop, driven by altered ERBB receptor activity, impacts treatment efficacy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling

Background:

  • The phosphoinositide 3-kinase (PI3K)/AKT and RAF/MEK/ERK pathways are frequently activated in human cancers.
  • Concomitant inhibition of these pathways is often required to impede cancer cell proliferation and induce tumor regression.
  • Feedback mechanisms can activate parallel pathways, diminishing the effectiveness of single-agent targeted therapies.

Purpose of the Study:

  • To elucidate a feedback mechanism where MEK inhibition activates PI3K/AKT signaling in EGFR and HER2-driven cancers.
  • To identify the molecular basis for this feedback loop and its impact on targeted therapy effectiveness.

Main Methods:

  • Investigated MEK inhibitor-induced signaling alterations in cancer models.
  • Analyzed ERBB receptor phosphorylation status and its effect on downstream signaling.
  • Utilized genetic mutations to assess the role of specific amino acid residues in feedback regulation.

Main Results:

  • MEK inhibition led to PI3K/AKT pathway activation in EGFR and HER2-driven cancers.
  • This activation was attributed to hyperactivation of ERBB3.
  • Loss of inhibitory threonine phosphorylation in EGFR and HER2 juxtamembrane domains caused increased ERBB receptor activity and PI3K/AKT upregulation.
  • Mutations preventing this phosphorylation rendered the ERBB3/PI3K/AKT pathway unresponsive to MEK inhibition.

Conclusions:

  • Identified a critical feedback network involving MEK and PI3K/AKT pathways in human cancers.
  • Demonstrated that alterations in ERBB receptor phosphorylation drive resistance to MEK inhibition.
  • This feedback mechanism represents a significant regulatory network in central oncogenic pathways.

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