Targeting Diffuse Large B-Cell Lymphoma with a Novel TRAIL-Based Chimeric Ligand: Mechanisms and Therapeutic Potential

TRAIL, a protein that induces apoptosis in cancer cells while sparing normal ones, holds promise as a therapeutic agent. However, clinical trials with TRAIL mimetics have shown limited success due to resistance. The novel chimeric protein AD-O51.4, which combines elements of TRAIL and a VEGFA-derived peptide, has been investigated for its cytotoxic effects in hematological malignancies.

In vitro assays were conducted to measure the sensitivity of various cancer types to AD-O51.4. The compound displayed significant cytotoxicity in diffuse large B-cell lymphoma (DLBCL) cells, inducing apoptosis through a death-receptor and caspase-dependent mechanism. However, this effect was not observed in other lymphoid malignancies or acute myeloid leukemia (AML) cell lines. The presence of death receptors and caspase 8 was identified as essential for AD-O51.4's apoptotic effect.

To explore resistance mechanisms, resistant cell lines were developed, and their transcriptomes were analyzed. The resistant cells showed alterations in gene expression related to apoptosis, endocytosis, and epigenetic regulation through HDAC pathways. These findings pointed toward potential sensitizing strategies, such as the use of HDAC inhibitors, BCL2 inhibitors, and endocytosis/dynamin inhibitors, which were confirmed to enhance the sensitivity of resistant DLBCL cells to AD-O51.4.

In conclusion, the research identified pharmacological strategies to overcome resistance to AD-O51.4, including the use of BCL2, HDAC inhibitors, and dynamin modulators. Given AD-O51.4's promising pharmacokinetics and safety profile, further clinical development is justified. Understanding resistance mechanisms in clinical practice could lead to personalized therapeutic approaches to enhance the effectiveness of AD-O51.4.