Cytotoxic efficacy and resistance mechanism of a trail and vegfa‐peptide fusion protein in colorectal cancer models

TNF‐related apoptosis‐inducing ligand (TRAIL) is a type II transmembrane protein capable of selectively inducing apoptosis in cancer cells by binding to its cognate receptors. Here, we examined the anticancer efficacy of a recently developed chimeric AD‐O51.4 protein, a TRAIL fused to the VEGFA‐originating peptide. We tested AD‐O51.4 protein activity against human col-orectal cancer (CRC) models and investigated the resistance mechanism in the non‐responsive CRC models. The quantitative comparison of apoptotic activity between AD‐O51.4 and the native TRAIL in nine human colorectal cancer cell lines revealed dose‐dependent toxicity in seven of them; the immunofluorescence‐captured receptor abundance correlated with the extent of apop-tosis. AD‐O51.4 reduced the growth of CRC patient‐derived xenografts (PDXs) with good efficacy. Cell lines that acquired AD‐O51.4 resistance showed a significant decrease in surface TRAIL receptor expression and apoptosis‐related proteins, including Caspase‐8, HSP60, and p53. These results demonstrate the effectiveness of AD‐O51.4 protein in CRC preclinical models and identify the potential mechanism underlying acquired resistance. Progression of AD‐O51.4 to clinical trials is expected.