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Venetoclax Overcomes Sorafenib Resistance in Acute Myeloid Leukemia by Targeting BCL2

Xi Xu1, Weiwei Ma2, Guo Qiu1

  • 1Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou 510091, China.

Biology
|October 27, 2023
PubMed

Insights

Sorafenib resistance in acute myeloid leukemia (AML) can be predicted using a gene signature. Combining sorafenib with venetoclax may overcome resistance by targeting the JAK-STAT3/BCL2 pathway in AML.

Area of Science:

  • Hematology
  • Oncology
  • Molecular Biology

Background:

  • Sorafenib, a kinase inhibitor, shows efficacy in acute myeloid leukemia (AML) but is often met with clinical resistance.
  • Mechanisms of sorafenib resistance and strategies to overcome it in AML remain incompletely understood.

Purpose of the Study:

  • To develop a platform for predicting sorafenib resistance and clinical outcomes in AML patients.
  • To identify effective therapeutic strategies to overcome sorafenib resistance in AML.

Main Methods:

  • Analysis of single-cell and bulk transcription data from sorafenib-resistant and control AML patients.
  • Integration of a sorafenib resistance gene signature for sensitivity and outcome prediction.
  • Drug sensitivity analysis of scRNA-seq data using deconvolution methods.

Main Results:

  • A sorafenib resistance gene signature was developed to predict AML cell sensitivity and patient outcomes.
  • Venetoclax demonstrated efficacy against sorafenib-resistant AML cells.
  • Sorafenib activates the JAK-STAT3 pathway, upregulating BCL2 expression in resistant AML cells, rendering them susceptible to venetoclax.

Conclusions:

  • A predictive platform for sorafenib resistance and clinical outcomes in AML was successfully developed.
  • The combination of sorafenib and venetoclax presents a promising therapeutic strategy for AML treatment, particularly in resistant cases.
Keywords:
BCL2acute myeloid leukemiachemoresistanceleukemiasorafenibvenetoclax

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