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Venetoclax Synergizes With Regorafenib for Colorectal Cancer by Targeting BCL-2

Lijun Zhu1, Weicheng Wang1,2, Yuwen Dong1

  • 1Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, The First Clinical Medical College of Nanjing Medical University, Nanjing Medical University, Nanjing, China.

Molecular Carcinogenesis
|July 24, 2025
PubMed

Insights

Combining regorafenib with venetoclax, a BCL-2 inhibitor, overcomes drug resistance in colorectal cancer (CRC). This combination therapy enhances antitumor effects by targeting angiogenesis and boosting immune responses, offering new treatment strategies for CRC patients.

Area of Science:

  • Oncology
  • Cancer Biology
  • Pharmacology

Background:

  • Colorectal cancer (CRC) patients often show poor response to regorafenib due to drug resistance.
  • The antiapoptotic protein B-cell lymphoma 2 (BCL-2) is implicated in various cancers and may contribute to treatment resistance.
  • Understanding the mechanisms of regorafenib resistance in CRC is crucial for developing effective therapies.

Purpose of the Study:

  • To investigate the role of BCL-2 in mediating regorafenib resistance in colorectal cancer.
  • To evaluate the efficacy of combining venetoclax (a BCL-2 antagonist) with regorafenib for CRC treatment.

Main Methods:

  • In vitro studies using colorectal cancer cell lines and human umbilical vein endothelial cells.
  • Assessment of cell proliferation, apoptosis, tumor angiogenesis, tumor blood vessel normalization, and immune cell infiltration.
  • Evaluation of the combined effect of regorafenib and venetoclax.

Main Results:

  • The combination of regorafenib and venetoclax significantly inhibited CRC cell proliferation and promoted apoptosis.
  • Combined treatment demonstrated anti-angiogenic effects, promoted tumor blood vessel normalization, and enhanced immune cell infiltration and cytotoxic factor release.
  • Venetoclax potentiated the antitumor activity of regorafenib.

Conclusions:

  • BCL-2 plays a significant role in promoting regorafenib resistance in colorectal cancer.
  • Combining regorafenib with venetoclax offers a promising therapeutic strategy for CRC by overcoming drug resistance.
  • These findings suggest a novel approach for clinical CRC treatment, repurposing venetoclax beyond its current use in hematological malignancies.
Keywords:
BCL‐2colorectal cancerregorafenibresistancevenetoclax

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