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Spatial and Temporal Analysis of Active ERK in the C. elegans Germline
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Induction of MEK/ERK activity by AZD8055 confers acquired resistance in neuroblastoma

Dong-Qing Xu1, Hidemi Toyoda1, Lei Qi1

  • 1Department of Pediatrics, Mie University Graduate School of Medicine, 2-174, Edobashi, Tsu, Mie, Japan.

Biochemical and Biophysical Research Communications
|March 25, 2018
PubMed

Insights

Acquiring resistance to the mTOR inhibitor AZD8055 in neuroblastoma cells was linked to MEK/ERK pathway activation. Combining AZD8055 with a MEK inhibitor effectively inhibited resistant neuroblastoma growth.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Mammalian target of rapamycin (mTOR) complex (mTORC) activation is common in cancers.
  • Dual mTORC1/2 inhibitors show promise, but drug resistance is a significant challenge.
  • AZD8055 is a specific mTOR kinase inhibitor blocking both mTORC1 and mTORC2.

Purpose of the Study:

  • To investigate the mechanisms of AZD8055 resistance in neuroblastoma (NB).
  • To evaluate combination therapy strategies to overcome AZD8055 resistance in NB.

Main Methods:

  • Developed AZD8055-resistant neuroblastoma cell sublines (TGW-R, SMS-KAN-R) through prolonged drug exposure.
  • Assessed resistance levels, cell cycle progression, and signaling pathway activation (MEK/ERK).
  • Evaluated the efficacy of combined AZD8055 and MEK inhibitor (U0126) treatment in vitro and in vivo.

Main Results:

  • Resistant NB cells (TGW-R, SMS-KAN-R) showed significantly higher resistance to AZD8055 compared to parent cells.
  • Resistant cells exhibited an advanced cell cycle G1/S transition.
  • AZD8055 resistance correlated with MEK/ERK signaling pathway over-activation.
  • Combination therapy with AZD8055 and U0126 significantly enhanced growth inhibition of resistant cells.

Conclusions:

  • MEK/ERK pathway over-activation is a key mechanism driving AZD8055 resistance in neuroblastoma.
  • Simultaneous targeting of mTOR kinase and MEK/ERK signaling is a potential strategy to overcome AZD8055 resistance in NB.
Keywords:
AZD8055MEK/ERKNeuroblastomaResistanceU0126mTOR kinase

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