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Identification of JNK1 as a predicting biomarker for ABT-199 and paclitaxel combination treatment

Ting Song1, Minhang Zhang2, Peng Liu2

  • 1State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian, China.

Biochemical Pharmacology
|June 29, 2018
PubMed

Insights

The combination of ABT-199 (Venetoclax) and paclitaxel shows synergistic effects in some cancers by enhancing apoptosis. Basal JNK1 levels can predict response to this combination therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Bcl-2 inhibition with ABT-199 (Venetoclax) has limited single-agent efficacy in many cancers.
  • Combination therapies are being explored to overcome resistance and enhance treatment outcomes.
  • Understanding synergistic mechanisms and identifying predictive biomarkers are crucial for effective cancer treatment.

Purpose of the Study:

  • To investigate the synergistic mechanism between ABT-199 and paclitaxel.
  • To identify biomarkers that predict tumor response to the ABT-199/paclitaxel combination.
  • To evaluate the efficacy of this combination across various cancer types.

Main Methods:

  • Combination Index (CI) assay was used to assess synergistic effects in nine cancer cell lines.
  • Analysis of Bcl-2 phosphorylation and its impact on ABT-199 efficacy.
  • Correlation analysis of JNK1 levels with CI values, including gene manipulation (overexpression/silencing).
  • Receiver Operating Characteristic (ROC) analysis to determine a biomarker cut-off value.

Main Results:

  • Four out of nine cancer cell lines exhibited synergistic responses to the ABT-199/paclitaxel combination, linked to enhanced intrinsic apoptosis.
  • Paclitaxel-induced Bcl-2 phosphorylation was found to impede the synergistic effect by preventing ABT-199 binding to phosphorylated Bcl-2 (pBcl-2).
  • Basal JNK1 level was identified as a predictive biomarker for pBcl-2 levels and synergistic response, with a preliminary cut-off value of 0.37.

Conclusions:

  • The combination of ABT-199 and paclitaxel can achieve synergistic anti-cancer effects through enhanced apoptosis.
  • Paclitaxel-induced Bcl-2 phosphorylation is a mechanism of resistance that can be overcome by identifying responsive tumors.
  • Basal JNK1 expression serves as a potential predictive biomarker for guiding the clinical application of this combination therapy.
Keywords:
ABT-199BiomarkerCombinationJNK1Paclitaxel

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