Selective targeting of mutant adenomatous polyposis coli (APC) in colorectal cancer
Menée in vitro et in vivo sur des modèles de cancer colorectal, cette étude met en évidence des mécanismes par lesquels un composé appelé TASIN-1 détruit de façon sélective les cellules cancéreuses présentant un gène APC muté
The adenomatous polyposis gene (APC), which is a tumor suppressor, is commonly mutated in colon cancer and cannot be directly targeted by existing therapeutics. Zhang et al. identified a drug called TASIN-1, which specifically targets cells with APC truncations, the most common APC mutation seen in colorectal cancer. The authors showed that this drug interferes with cholesterol biosynthesis and that it selectively kills APC-truncated cancer cells in vitro and in mouse models without any detectable toxicity, paving the way for further development of TASIN-1. Mutations in the adenomatous polyposis coli (APC) gene are common in colorectal cancer (CRC), and more than 90% of those mutations generate stable truncated gene products. We describe a chemical screen using normal human colonic epithelial cells (HCECs) and a series of oncogenically progressed HCECs containing a truncated APC protein. With this screen, we identified a small molecule, TASIN-1 (truncated APC selective inhibitor–1), that specifically kills cells with APC truncations but spares normal and cancer cells with wild-type APC. TASIN-1 exerts its cytotoxic effects through inhibition of cholesterol biosynthesis. In vivo administration of TASIN-1 inhibits tumor growth of CRC cells with truncated APC but not APC wild-type CRC cells in xenograft models and in a genetically engineered CRC mouse model with minimal toxicity. TASIN-1 represents a potential therapeutic strategy for prevention and intervention in CRC with mutant APC.