TASIN (Truncated APC-Selective Inhibitors) compounds are selectively toxic to colorectal cancer cells with APC mutations, although their mechanism of action remains unknown. Here, we found that TASINs inhibit three enzymes in the post-squalene cholesterol biosynthetic pathway including EBP, DHCR7, and DHCR24. Even though all three of these enzymes are required for cholesterol biosynthesis, only inhibition of the most upstream enzyme, EBP, led to cancer cell death via depletion of downstream sterols, an observation that was confirmed by genetic silencing of EBP. Pharmacologic inhibition or genetic silencing of either DHCR7 or DHCR24 had no impact on cell viability. By using photo-affinity probes to generate a relationship between chemical structure and probe competition, we identified compounds that selectively inhibit either EBP or DHCR7. These studies identify EBP, but not downstream enzymes in the cholesterol biosynthetic pathway, as a target in APC mutant colorectal cancer and also have implications for the clinical development of highly selective EBP inhibitors.
Lymphovascular Infiltration, Not Depth of Invasion, is the Critical Risk Factor of Metastases in Early Colorectal Cancer: Retrospective Population-based Cohort Study on Prospectively Collected Data, Including Validation.
March 19, 2020
- ASCO – Lung CancerASCO.20 Virtual Scientific Program, held May 29 - 31, brought professionals from all over the world together to hear the brightest minds in oncology present state-of-the-art treatment modalities and new therapies.
- AACR-2020The American Association for Cancer Research is the world's oldest and largest professional association related to cancer research.
- ACC 2020The American College of Cardiology decided to cancel ACC.20/WCC due to COVID-19, which was scheduled to take place March 28-30 in Chicago. However, ACC.20/WCC Virtual Meeting continues to release cutting edge science and practice changing updates for cardiovascular professionals on demand and free through June 2020.
- ASCO 2019The 2019 ASCO Annual Meeting, taking place May 31-June 4 in Chicago, will bring together more than 32,000 oncology professionals from across the globe. The theme of this year’s conference is Caring for Every Patient, Learning From Every Patient.