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Purification of Ubiquitinated p53 Proteins from Mammalian Cells
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Purification of Ubiquitinated p53 Proteins from Mammalian Cells

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The p53 activator overcomes resistance to ALK inhibitors by regulating p53-target selectivity in ALK-driven

Makoto Miyazaki1,2,3,4, Ryo Otomo1,5, Yuko Matsushima-Hibiya1,4

  • 11Division of Refractory and Advanced Cancer, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045 Japan.

Cell Death Discovery
|May 16, 2018
PubMed

Insights

Combining anaplastic lymphoma kinase (ALK) inhibitors with a p53 activator overcomes resistance in ALK-driven neuroblastomas. This novel therapy shifts cancer cells from cell cycle arrest to apoptosis, preventing tumor relapse.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Anaplastic lymphoma kinase (ALK) is a key driver in neuroblastomas, often activated by gene amplification or mutation.
  • ALK inhibitors are effective but limited by the development of drug resistance.
  • Developing strategies to overcome ALK inhibitor resistance is crucial for improving patient outcomes.

Purpose of the Study:

  • To investigate the potential of combining ALK inhibitors with p53 activators to overcome resistance in ALK-driven neuroblastomas.
  • To elucidate the molecular mechanisms underlying the synergistic effect of combination therapy.

Main Methods:

  • Utilized in vitro and in vivo models of ALK-driven neuroblastomas.
  • Administered combination treatment with an ALK inhibitor and a p53 activator.
  • Analyzed cell cycle progression, apoptosis induction, and tumor relapse.
  • Investigated the role of the ALK-AKT-FOXO3a signaling pathway and SOX4 expression.

Main Results:

  • Combination treatment with ALK inhibitor and p53 activator attenuated ALK inhibitor resistance.
  • This combination therapy induced apoptosis and prevented tumor relapse, unlike monotherapy which caused cell cycle arrest.
  • The mechanism involves the ALK-AKT-FOXO3a axis inhibition, leading to SOX4 upregulation.
  • SOX4, in conjunction with p53, enhances the expression of the pro-apoptotic protein PUMA.

Conclusions:

  • Combination therapy with ALK inhibitors and p53 activators represents a promising strategy for treating ALK-driven neuroblastomas.
  • This approach effectively overcomes drug resistance by inducing apoptosis through the SOX4-PUMA axis.
  • Further clinical investigation is warranted to validate this novel therapeutic approach.

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