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

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.

Comparative Proteogenomic Analysis of Right-sided Colon Cancer, Left-sided Colon Cancer and Rectal Cancers Reveal Distinct Mutational Profiles

“…Given the recent findings by Zhang et al demonstrating the efficacy of TASIN-1(small molecule inhibitor) in a murine xenograft model of human colorectal cancer harboring a truncation mutation (A1309*) similar to APC R1450* suggests that this mutation may be biologically relevant. [45,46]…”

Abstract A31: Targeting APC loss using synthetic lethality in Colorectal Cancer

“…Additionally an APC mutation alone is thought to not be sufficient for a cell line to become fully tumourigenic, the cell line would not have any of the additional mutations in key pathways characteristic of CRC and this would have increased the risk that our findings did not translate to a panel of CRC cell lines (Matano et al 2015). A recent paper used a normal HCEC cell line known as 1CT and the normal colon cell line was modified using a combination of shRNA against TP53 and APC, alongside ectopically expressing plasmids for KRAS G12V and APC1309 (Zhang et al 2016). This model successfully identified the drug TASIN-1 which shows a synthetic lethal relationship with the APC mutation.…”

“…A recent paper has identified truncated APC selective inhibitor-1 (TASIN-1) as a compound which induces apoptotic cell death in APC mutant CRC (Zhang et al 2016).…”

“…Both cell lines expressed KRAS G12V, TP53 shRNA, APC shRNA and one of the lines additionally ectopically expressed APC1309 truncation. This resulted in two cell Introduction Page lines known as ICTRPA and ICTRPA A1309 which differed just in the presence of truncated APC (Zhang et al 2016). TASIN-1 was then shown to be effective in other models including commonly used APC mutant CRC cell lines, xenograft models (using APC mutant HT29 and DLD1 cell lines) and the mouse model APC 580 .TASIN-1 was identified to potentially target emopamil-binding protein (EBP) which is part of the cholesterol synthesis pathway (downstream of 3-hydroxyl-3-methylglutaryl coenzyme A reductase (HMGCR)).…”

“…TASIN-1 was then shown to be effective in other models including commonly used APC mutant CRC cell lines, xenograft models (using APC mutant HT29 and DLD1 cell lines) and the mouse model APC 580 .TASIN-1 was identified to potentially target emopamil-binding protein (EBP) which is part of the cholesterol synthesis pathway (downstream of 3-hydroxyl-3-methylglutaryl coenzyme A reductase (HMGCR)). In APC mutant cell lines cholesterol synthesis decreases upon TASIN-1 treatment and these cell lines are unable to respond to this decrease because they are unable to upregulate sterol regulatory element-binding protein 2 (SREBP2) and SREBP2 target genes (Zhang et al 2016). This study shows promise in developing a targeted therapy specific for patients with APC mutations.…”