Selective targeting of mutant adenomatous polyposis coli (APC) in colorectal cancer

Sci Transl Med. 2016 Oct 19;8(361):361ra140. doi: 10.1126/scitranslmed.aaf8127.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomatous Polyposis Coli Protein / genetics*
  • Animals
  • Cell Proliferation
  • Cholesterol / chemistry
  • Colonic Neoplasms / genetics*
  • Colonic Neoplasms / pathology
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • Female
  • Genes, Tumor Suppressor
  • HCT116 Cells
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Molecular Targeted Therapy*
  • Mutation
  • Piperidines / pharmacology*
  • Sterol Regulatory Element Binding Protein 2 / metabolism
  • Sulfonamides / pharmacology*
  • Transgenes
  • Xenograft Model Antitumor Assays


  • Adenomatous Polyposis Coli Protein
  • Piperidines
  • SREBF2 protein, human
  • Sterol Regulatory Element Binding Protein 2
  • Sulfonamides
  • TASIN-1 compound
  • Cholesterol