Department of Human Anatomy, School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, Sichuan, China.
Department of Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China.
Eur J Cancer. 2022 Apr;165:58-70. doi: 10.1016/j.ejca.2022.01.004. Epub 2022 Feb 23.
BRAF and MEK inhibitors significantly prolonged the progression-free survival of patients with BRAF mutant melanoma, but their long-term efficacy was limited by drug resistance. Our previous studies found that targeted inhibition of the mitogen-activated protein kinases (MAPK) pathway promotes the activation of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway in BRAF-mutant melanoma cells. Whether dual inhibition of MAPK and JAK2/STAT3 pathways can reverse drug resistance in melanoma remains unclear.
This study verified whether morusin could enhance the inhibitory effect of MAPK pathway inhibitors on BRAF mutant melanoma by inhibiting the feedback activation of STAT3 at the cellular and animal levels.
We demonstrated that morusin could enhance the inhibitory effect of MAPK pathway inhibitors on BRAF mutant melanoma cells by inhibiting the feedback activation of the STAT3/SOX2 pathway. Moreover, our study showed morusin combined with MAPK pathway inhibitors specifically inhibited BRAF-mutant melanoma cells to a greater extent than wild-type cells. Our results also showed that the combination of morusin and BRAF inhibitors could jointly inhibit BRAF mutant melanoma in vivo. Finally, our experiment also revealed that the combination therapy of morusin and MAPK pathway inhibitors jointly inhibited drug-resistant melanoma in vitro and in vivo.
Our results suggested that the combination of morusin and MAPK pathway inhibitors may be a more effective treatment strategy for BRAF-mutant melanoma than MAPK pathway inhibitors alone.
BRAF 和 MEK 抑制剂显著延长了 BRAF 突变型黑色素瘤患者的无进展生存期，但它们的长期疗效受到耐药性的限制。我们之前的研究发现，靶向抑制丝裂原活化蛋白激酶（MAPK）通路会促进 BRAF 突变型黑色素瘤细胞中 Janus 激酶 2/信号转导和转录激活因子 3（JAK2/STAT3）通路的激活。双重抑制 MAPK 和 JAK2/STAT3 通路是否能逆转黑色素瘤的耐药性尚不清楚。
本研究在细胞和动物水平上验证了莫诺苷是否可以通过抑制 STAT3 的反馈激活来增强 MAPK 通路抑制剂对 BRAF 突变型黑色素瘤的抑制作用。
我们证明了莫诺苷通过抑制 STAT3/SOX2 通路的反馈激活，增强了 MAPK 通路抑制剂对 BRAF 突变型黑色素瘤细胞的抑制作用。此外，我们的研究还表明，莫诺苷联合 MAPK 通路抑制剂特异性地抑制 BRAF 突变型黑色素瘤细胞的程度大于野生型细胞。我们的结果还表明，莫诺苷和 BRAF 抑制剂的联合治疗可以共同抑制体内的 BRAF 突变型黑色素瘤。最后，我们的实验还揭示了莫诺苷和 MAPK 通路抑制剂联合治疗在体外和体内共同抑制耐药性黑色素瘤。
我们的研究结果表明，莫诺苷和 MAPK 通路抑制剂的联合治疗可能是一种比单独使用 MAPK 通路抑制剂更有效的治疗 BRAF 突变型黑色素瘤的策略。
