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

Despite notable advancements in therapeutic modalities, many patients with colorectal Cancer (CRC) exhibit inadequate response to regorafenib, largely due to the propensity for drug resistance. Deeper insights into the mechanism of CRC sensitivity to regorafenib therapy are urgently required. The antiapoptotic protein B-cell lymphoma 2 (Bcl-2) is closely associated with a variety of malignancies. Therefore, this study investigated the role of Bcl-2 in promoting regorafenib resistance in colorectal Cancer. Venetoclax, a Bcl-2 Antagonist, potentiates the antitumor activity of regorafenib. The combination of regorafenib and Venetoclax inhibited the proliferation and promoted Apoptosis of CRC cells and human umbilical vein endothelial cells in vitro by inhibiting tumor angiogenesis, promoting normalization of tumor blood vessels, and promoting immune cell infiltration and the release of immune cytotoxic factors. Although Venetoclax is primarily used clinically to treat hematological tumors, it has not yet been used to treat CRC. These findings provide new insights for the clinical treatment of CRC.

BCL‐2; colorectal cancer; regorafenib; resistance; venetoclax.