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Conditional drug screening shows that mitotic inhibitors induce AKT/PKB-insensitive apoptosis

Maria Berndtsson1, Emma Hernlund, Maria C Shoshan

  • 1Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institute and Hospital, Cancer Center Karolinska, R8:00, S-171 76, Stockholm, Sweden.

Journal of Chemical Biology
|July 2, 2009
PubMed

Insights

This study identified cancer drug mechanisms insensitive to the PI3K/AKT pathway. Drugs targeting mitosis induce apoptosis, offering potential for overcoming chemotherapy resistance in cancers with activated AKT1.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is often overactive in human cancers.
  • Activation of the PI3K/AKT pathway is linked to resistance against chemotherapy.

Purpose of the Study:

  • To identify apoptotic mechanisms that remain effective despite PI3K/AKT pathway activation.
  • To find anticancer agents that can overcome AKT1-mediated drug resistance.

Main Methods:

  • Screened the National Cancer Institute (NCI) Mechanistic Set drug library against colon carcinoma cells with active AKT1.
  • Classified compounds by mechanism of action using NCI Developmental Therapeutics Program (DTP) data.
  • Employed a chemical biology and chemical informatics approach.

Main Results:

  • Compounds interfering with the mitotic process induced apoptosis.
  • This mitotic-targeting apoptosis was relatively insensitive to constitutive AKT1 activity.
  • Identified a subset of drugs effective against AKT1-activated cancer cells.

Conclusions:

  • Drugs targeting the cell's mitotic process may overcome resistance mediated by the PI3K/AKT pathway.
  • This screening strategy can reveal drug sensitivities based on specific pathway activation states.
  • Findings aid in developing more effective cancer therapies for resistant tumors.

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