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Derivation of Thymic Lymphoma T-cell Lines from Atm-/- and p53-/- Mice
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ERK-dependent IL-6 positive feedback loop mediates resistance against a combined treatment using danusertib and

Jun Liu1, Junshik Hong1,2,3, Kwang-Sung Ahn4

  • 1Cancer Research Institute, Seoul National University College of Medicine , Seoul , Republic of Korea.

Leukemia & Lymphoma
|April 6, 2019
PubMed

Insights

The PI3K inhibitor BKM120 combined with danusertib showed synergistic effects in Burkitt lymphoma cells. Resistance developed via an ERK/IL-6 feedback loop, highlighting a mechanism for adaptive resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Burkitt lymphoma is an aggressive non-Hodgkin lymphoma.
  • Targeting PI3K and Aurora kinases is a therapeutic strategy.
  • Understanding resistance mechanisms is crucial for effective treatment.

Purpose of the Study:

  • To investigate the synergistic effects of BKM120 and danusertib in Burkitt lymphoma.
  • To elucidate the resistance mechanisms to combined PI3K and Aurora kinase inhibition.

Main Methods:

  • Cell lines: Namalwa and BJAB (Burkitt lymphoma).
  • Inhibitors: BKM120 (PI3K inhibitor), danusertib (pan-Aurora kinase inhibitor), trametinib (ERK inhibitor).
  • Assays: Synergy assessment, Western blotting, IL-6 and IL-6R mRNA expression analysis, chemoresistance evaluation.

Main Results:

  • Danusertib and BKM120 combination demonstrated synergistic effects in Namalwa cells, but not BJAB cells.
  • Combined treatment induced ERK hyperactivation and IL-6 secretion in BJAB cells.
  • Trametinib blockade of ERK signaling improved antitumor effects by reducing IL-6 expression.
  • Stepwise treatment induced chemoresistance in Namalwa cells via an ERK/IL-6 feedback loop.

Conclusions:

  • The ERK/IL-6 feedback loop contributes to adaptive resistance and relapse in Burkitt lymphoma.
  • This feedback loop can compensate for AKT inactivation.
  • Targeting this loop may overcome resistance to PI3K and Aurora kinase inhibitors.
Keywords:
Aurora kinaseBKM120Burkitt lymphomaPI3Kchemoresistancedanusertib

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