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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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Oncogenic PI3K/AKT promotes the step-wise evolution of combination BRAF/MEK inhibitor resistance in melanoma

Mal Irvine1,2, Ashleigh Stewart1,2, Bernadette Pedersen1,2

  • 1Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia.

Oncogenesis
|September 22, 2018
PubMed

Insights

Melanoma patients on targeted therapies often develop resistance. This study reveals that PI3K/AKT pathway activation promotes survival of dormant cells, which later reactivate MAPK signaling for resistance to multiple therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • BRAF-mutant melanoma frequently develops resistance to BRAF and BRAF/MEK inhibitor therapies within a year.
  • Resistance typically involves MAPK pathway reactivation through BRAF, NRAS, or MEK1/2 alterations.
  • A subset of resistant melanomas activates the compensatory PI3K/AKT signaling pathway.

Purpose of the Study:

  • To investigate the role of PI3K/AKT signaling in melanoma resistance to BRAF/MEK inhibitors.
  • To determine if PI3K/AKT activation can overcome proliferative arrest induced by BRAF/MEK inhibition.
  • To elucidate the mechanisms by which PI3K/AKT signaling contributes to the evolution of drug resistance.

Main Methods:

  • Utilized melanoma cell lines with BRAF/MEK inhibition.
  • Introduced oncogenic PIK3CA and AKT3 mutants to assess PI3K/AKT pathway activation.
  • Monitored MAPK signaling reactivation and dependence on PI3K/AKT signaling during resistance evolution.

Main Results:

  • PI3K/AKT signaling, even with potent mutants, did not overcome BRAF/MEK inhibitor-induced proliferative arrest.
  • Activation of PI3K/AKT signaling enabled survival of dormant MAPK-inhibited melanoma cells.
  • Evolved resistance involved MAPK reactivation, independent of the initial PI3K/AKT-activating oncogene.

Conclusions:

  • PI3K/AKT pathway activation promotes melanoma cell survival under targeted therapy by maintaining a dormant state.
  • This survival mechanism facilitates the evolution of resistance, characterized by altered signaling dependence.
  • These findings suggest a dynamic resistance model that could lead to tumor subclones resistant to multiple targeted therapies.

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