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.
Lu Zhang  1 ,  Panayotis C Theodoropoulos  2 ,  Ugur Eskiocak  3 ,  Wentian Wang  2 ,  Young-Ah Moon  4 ,  Bruce Posner  2 ,  Noelle S Williams  2 ,  Woodring E Wright  1 ,  Sang Bum Kim  1 ,  Deepak Nijhawan  2  5  6 ,  Jef K De Brabander  2 ,  Jerry W Shay  7
Affiliations
  • 1. Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 2. Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 3. Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 4. Department of Molecular Medicine, Inha University College of Medicine, 100 Inha-ro, Nam-gu, Incheon 22212, Korea.
  • 5. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 6. Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 7. Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. [email protected].
PMID: 27798265 DOI: 10.1126/scitranslmed.aaf8127
Abstract

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.

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