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.
摘要:
BRAFV600E突变常见于癌症。它激活MAPK通路并促进癌细胞增殖,使BRAF成为抗癌治疗的良好靶点。虽然BRAF靶向治疗对黑色素瘤非常有效,它通常对携带BRAF突变的其他癌症无效。在这项研究中,我们评估了蛋白水解靶向嵌合体(PROTAC)的有效性,SJF-0628,指导突变的BRAF在不同的癌细胞组中的降解,并确定这些细胞如何响应降解。SJF-0628处理导致BRAFV600E的降解和所有测试细胞系中Mek活化的降低,但治疗对细胞信号传导和细胞增殖的影响是细胞系特异性的。首先,BRAF降解通过凋亡杀死DU-4475和Colo-205细胞,但仅部分抑制其他癌细胞系的增殖。第二,SJF-0628处理导致Colo-205细胞中MEK的共降解,但在其他细胞系中没有相同的作用。最后,受BRAF降解部分抑制的细胞系还含有其他致癌驱动因素,使它们成为多驱动癌细胞。这些结果证明了PROTAC指导BRAF降解的实用性,并揭示了多驱动因子肿瘤发生使一些结直肠癌细胞对BRAF靶向治疗具有抗性。