Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Acta Biochim Biophys Sin (Shanghai). 2018 Apr 1;50(4):355-361. doi: 10.1093/abbs/gmy018.
Mutations in the oncogene BRAF(V600E) are found in ~10% of colorectal cancers (CRCs) and are associated with poor prognosis. However, BRAF(V600E) has a limited response to the small-molecule drug, vemurafenib, a BRAF inhibitor, and BRAF inhibition is thought to cause a feedback activation of EGFR signaling that supports continued proliferation. In this study, we explored the effect of combined use of dabrafenib, a BRAF inhibitor, and cetuximab, an EGFR inhibitor, on BRAF(V600E)-mutant CRC stem cells and its possible mechanisms. Through cell viability analysis, flow cytometry, sphere forming, and western blot analysis, we found that the dabrafenib can synergize with cetuximab to reduce cell viability, induce enhanced apoptotic rates and cell cycle arrest in BRAF(V600E)-mutant HT-29 cells and inhibits stem cell capacities. Further, western blot analysis revealed that PTEN/Src/c-Myc pathway is possibly involved in the synergism between dabrafenib and cetuximab. Overall, our study shows that the combination of dabrafenib and cetuximab results in increased antitumor activity and decreased stem cell capacities in BRAF(V600E)-mutant CRC cells.
BRAF(V600E) 基因突变存在于约 10%的结直肠癌（CRC）中，与不良预后相关。然而，BRAF(V600E) 对小分子药物 vemurafenib（一种 BRAF 抑制剂）的反应有限，而 BRAF 抑制被认为会导致 EGFR 信号的反馈激活，从而支持持续增殖。在这项研究中，我们探讨了 BRAF 抑制剂 dabrafenib 和 EGFR 抑制剂 cetuximab 联合使用对 BRAF(V600E)突变型 CRC 干细胞的影响及其可能的机制。通过细胞活力分析、流式细胞术、球体形成和 Western blot 分析，我们发现 dabrafenib 可与 cetuximab 协同作用，降低 BRAF(V600E)突变型 HT-29 细胞的细胞活力，诱导增强的凋亡率和细胞周期停滞，并抑制干细胞能力。进一步的 Western blot 分析表明，PTEN/Src/c-Myc 通路可能参与了 dabrafenib 和 cetuximab 的协同作用。总的来说，我们的研究表明，dabrafenib 和 cetuximab 的联合使用可增强 BRAF(V600E)突变型 CRC 细胞的抗肿瘤活性并降低其干细胞能力。
