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Sci Transl Med. 2016 Oct 19;8(361):361ra140.

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

Author information

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. jerry.shay@utsouthwestern.edu.

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.

PMID:
27798265
DOI:
10.1126/scitranslmed.aaf8127
[Indexed for MEDLINE]

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