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

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Adenomatous polyposis coli (APC) gene mutations are prevalent in colorectal cancer (CRC), often resulting in truncated APC proteins.
• Targeting specific genetic alterations in cancer offers a promising therapeutic avenue.

Purpose of the Study:

• To identify a small molecule that selectively eliminates cancer cells with truncated APC.
• To investigate the therapeutic potential of TASIN-1 in colorectal cancer models.

Main Methods:

• Chemical screening of normal and oncogenically progressed human colonic epithelial cells (HCECs).
• In vitro and in vivo testing of TASIN-1 efficacy and toxicity in colorectal cancer models.
• Analysis of TASIN-1's mechanism of action, focusing on cholesterol biosynthesis.

Main Results:

• TASIN-1 selectively induced cell death in HCECs and CRC cells with truncated APC, sparing normal and wild-type APC cells.
• TASIN-1 demonstrated significant inhibition of tumor growth in xenograft and genetically engineered mouse models of CRC with mutant APC.
• TASIN-1's mechanism involves the inhibition of cholesterol biosynthesis.

Conclusions:

• TASIN-1 is a potent and selective inhibitor of colorectal cancer cells harboring truncated APC mutations.
• TASIN-1 exhibits therapeutic potential for CRC prevention and intervention with a favorable safety profile.
• Targeting cholesterol biosynthesis represents a viable strategy for treating APC-mutant colorectal cancer.