{Reference Type}: Journal Article
{Title}: The Targeted Degradation of BRAF V600E Reveals the Mechanisms of Resistance to BRAF-Targeted Treatments in Colorectal Cancer Cells.
{Author}: Chapdelaine AG;Ku GC;Sun G;Ayrapetov MK;
{Journal}: Cancers (Basel)
{Volume}: 15
{Issue}: 24
{Year}: 2023 Dec 12
{Factor}: 6.575
{DOI}: 10.3390/cancers15245805
{Abstract}: The BRAF V600E mutation is frequently found in cancer. It activates the MAPK pathway and promotes cancer cell proliferation, making BRAF an excellent target for anti-cancer therapy. While BRAF-targeted therapy is highly effective for melanoma, it is often ineffective against other cancers harboring the BRAF mutation. In this study, we evaluate the effectiveness of a proteolysis targeting chimera (PROTAC), SJF-0628, in directing the degradation of mutated BRAF across a diverse panel of cancer cells and determine how these cells respond to the degradation. SJF-0628 treatment results in the degradation of BRAF V600E and a decrease in Mek activation in all cell lines tested, but the effects of the treatment on cell signaling and cell proliferation are cell-line-specific. First, BRAF degradation killed DU-4475 and Colo-205 cells via apoptosis but only partially inhibited the proliferation of other cancer cell lines. Second, SJF-0628 treatment resulted in co-degradation of MEK in Colo-205 cells but did not have the same effect in other cell lines. Finally, cell lines partially inhibited by BRAF degradation also contain other oncogenic drivers, making them multi-driver cancer cells. These results demonstrate the utility of a PROTAC to direct BRAF degradation and reveal that multi-driver oncogenesis renders some colorectal cancer cells resistant to BRAF-targeted treatment.