Affiliation:
1. Department of Cell and Molecular Biology, University of Rhode Island, Kingston, RI 02881, USA
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.
Funder
the United States Department of Defense Peer-Reviewed Cancer Research Program
Reference61 articles.
1. Targeting the Raf kinases in human cancer: The Raf dimer dilemma;Durrant;Br. J. Cancer,2018
2. Mutations of the BRAF gene in human cancer;Davies;Nature,2002
3. Discovery of Selective Small Molecule Degraders of BRAF-V600E;Han;J. Med. Chem.,2020
4. Regulation of RAF protein kinases in ERK signalling;Lavoie;Nat. Rev. Mol. Cell Biol.,2015
5. Mauri, G., Bonazzina, E., Amatu, A., Tosi, F., Bencardino, K., Gori, V., Massihnia, D., Cipani, T., Spina, F., and Ghezzi, S. (2021). The Evolutionary Landscape of Treatment for. Cancers, 13.
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