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Strategic Therapeutic Targeting to Overcome Venetoclax Resistance in Aggressive B-cell Lymphomas

Lan V Pham1, Shengjian Huang2, Hui Zhang2

  • 1Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. miwang@mdanderson.org liazhang@mdanderson.org lvpham@mdanderson.org.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|April 19, 2018
PubMed

Insights

The BCL-2 inhibitor venetoclax shows efficacy in aggressive B-cell lymphomas. Targeting the PI3K/AKT pathway can overcome venetoclax resistance, offering new therapeutic strategies for diffuse large B-cell lymphoma and mantle cell lymphoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • B-cell lymphoma-2 (BCL-2) is an antiapoptotic protein frequently dysregulated in B-cell lymphomas.
  • Venetoclax, a BCL-2 inhibitor, has shown promise in early clinical trials for non-Hodgkin lymphoma.

Purpose of the Study:

  • To investigate the biological effects and mechanism of action of venetoclax in aggressive B-cell lymphomas, specifically mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL).
  • To identify biomarkers for venetoclax activity and explore combination therapies to enhance treatment response.

Main Methods:

  • Utilized MCL and DLBCL cell lines, primary patient samples, and patient-derived xenograft (PDX) models to assess venetoclax efficacy.
  • Employed proteomics analysis and Western blotting to evaluate mechanisms of response and resistance to venetoclax.

Main Results:

  • High BCL-2 expression correlated with sensitivity to venetoclax in cell lines, patient samples, and PDX models.
  • Venetoclax treatment altered key protein expression and phosphorylation involved in DNA damage response, metabolism, cell growth, and apoptosis.
  • Inhibition of PTEN by venetoclax led to increased AKT pathway activation, making cells susceptible to PI3K/AKT inhibition, even in resistant cells.

Conclusions:

  • Venetoclax demonstrates on-target effects in aggressive B-cell lymphomas.
  • PI3K/AKT inhibition presents a viable strategy to overcome both acquired and intrinsic venetoclax resistance.

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