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Leo I. Gordon, MD, FACP

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AACR 2022: Can Decitabine Sensitize DLBCL Cells to Venetoclax?

By: Lauren Harrison, MS
Posted: Monday, April 11, 2022

The DNA hypomethylating agent decitabine appears to be able to sensitize diffuse large B-cell lymphoma (DLBCL) cells to the BCL2 inhibitor venetoclax in vivo, researchers have found, possibly by increasing apoptotic priming and dependence on the BCL2 gene. Fen Zhu, PhD, of Dana-Farber Cancer Institute, Boston, presented this work on behalf of colleagues at the American Association for Cancer Research (AACR) Annual Meeting 2022 (Abstract 5377). The authors suggest further study of this combination in in vivo model systems is warranted.

This study used a functional assay to understand how the mitochondria were primed for apoptosis and the dependence of the B-cell lines on the antiapoptotic BCL2 family of proteins. Several DLBCL cell lines and double hit patient-derived xenograft cell lines were used to assess the in vitro anticancer activity of venetoclax and decitabine as well.

The DLBCL cells were noted to be heterogeneously dependent on BCL2-proteins and had variable expression of these antiapoptotic proteins on Western blot. The cells were less sensitive to single BH3 mimetic treatment with venetoclax; however, decitabine was found to prime the cells for apoptosis and increase dependence on BCL2, therefore increasing the sensitivity of the B cells to venetoclax. The combination of venetoclax and decitabine acted synergistically to induce apoptosis and suppress cell proliferation.

Decitabine is known to increase TGF-β signaling in DLBCL by restoration of SMAD1, a downstream target. However, according to the researchers, inhibition of TGF-β only partially interfered with the anticancer activity of decitabine, indicating other mechanisms of action seem to exist for decitabine. Researchers found that decitabine also produced DNA damage, leading to cell-cycle arrest in cancer cells, and promoted the activation of BAK and BAX, two key apoptotic effector proteins. In addition, the combination of venetoclax and decitabine suppressed oxidative phosphorylation in the cancer cells and thereby restricted the energy supply needed for cell proliferation.

Disclosure: For a full list of authors’ disclosures, visit abstractsonline.com.


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