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

Lu Zhang, Panayotis C. Theodoropoulos, Ugur Eskiocak, Wentian Wang, Young Ah Moon, Bruce Posner, Noelle S. Williams, Woodring E. Wright, Sang Bum Kim, Deepak Nijhawan, Jef K. De Brabander, Jerry W. Shay

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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. 2016

Original languageEnglish (US)
Article number361ra140
JournalScience Translational Medicine
Volume8
Issue number361
DOIs
StatePublished - Oct 19 2016

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ASJC Scopus subject areas

  • Medicine(all)

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