TheBRAFV600E 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 theBRAFmutation. 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.
BRAF V600E突变在多种癌症中频繁出现。该突变通过激活MAPK通路促进癌细胞增殖，使BRAF成为抗癌治疗的理想靶点。尽管BRAF靶向疗法对黑色素瘤疗效显著，但对携带该突变的其他癌症类型往往效果有限。本研究评估了蛋白水解靶向嵌合体（PROTAC）SJF-0628在多种癌细胞系中诱导突变型BRAF降解的效果，并探究了细胞对降解过程的响应机制。实验结果显示，SJF-0628处理能导致所有测试细胞系中的BRAF V600E降解并降低Mek活化水平，但其对细胞信号传导和增殖的影响具有细胞系特异性：首先，BRAF降解通过细胞凋亡途径完全抑制DU-4475和Colo-205细胞增殖，而对其他癌细胞系仅产生部分抑制作用；其次，SJF-0628处理在Colo-205细胞中引起MEK共降解现象，但在其他细胞系中未观察到相同效应；最后，对BRAF降解仅产生部分响应的细胞系同时存在其他致癌驱动因子，属于多驱动型癌细胞。本研究证实了PROTAC技术介导BRAF降解的应用价值，同时揭示多驱动致癌机制导致部分结直肠癌细胞对BRAF靶向治疗产生耐药性。
肿瘤(癌症)患者之家