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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
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The path to venetoclax resistance is paved with mutations, metabolism, and more

Graeme P Sullivan1, Lyndsey Flanagan1, Daniel Alencar Rodrigues1

  • 1Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Ireland.

Science Translational Medicine
|December 8, 2022
PubMed

Insights

Venetoclax resistance in chronic lymphocytic leukemia (CLL) and acute myelogenous leukemia (AML) is a growing problem. Understanding resistance mechanisms and combination therapies is key to improving patient outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Venetoclax, a B-cell lymphoma 2 (BCL-2)-selective antagonist, shows promise in treating chronic lymphocytic leukemia (CLL) and acute myelogenous leukemia (AML).
  • However, a significant challenge is the development of resistance and subsequent disease relapse in patients treated with venetoclax.

Purpose of the Study:

  • To summarize emerging mechanisms of venetoclax resistance in hematological malignancies.
  • To discuss promising combination strategies to overcome venetoclax resistance.
  • To highlight venetoclax combination therapies currently undergoing clinical trials.

Main Methods:

  • Literature review and synthesis of preclinical and clinical data.
  • Analysis of emerging resistance pathways.
  • Identification and categorization of combination therapies.

Main Results:

  • Several mechanisms contribute to venetoclax resistance, including alterations in BCL-2 family proteins and drug efflux pumps.
  • Combination strategies involving venetoclax with other targeted agents or chemotherapy show potential in preclinical models.
  • Multiple venetoclax combination trials are ongoing in CLL and AML patients.

Conclusions:

  • Understanding venetoclax resistance mechanisms is crucial for developing effective therapeutic strategies.
  • Targeted combination therapies hold promise for overcoming resistance and improving treatment outcomes in CLL and AML.
  • Further research into BCL-2 biology in cancer is essential for advancing targeted treatments.

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