Morusin enhances the antitumor activity of MAPK pathway inhibitors in BRAF-mutant melanoma by inhibiting the feedback activation of STAT3

Background: 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 BRAFmutant melanoma cells. Whether dual inhibition of MAPK and JAK2/STAT 3 pathways can reverse drug resistance in melanoma remains unclear. Methods: 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. Results: 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. Conclusion: 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. (c) 2022 Southwest Medical University. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

This study found that morusin can enhance the inhibitory effect of MAPK pathway inhibitors on BRAF mutant melanoma cells by inhibiting the feedback activation of the STAT3/SOX2 pathway. The combination of morusin and MAPK pathway inhibitors shows greater efficacy in inhibiting BRAF-mutant melanoma and drug-resistant melanoma compared to the use of MAPK pathway inhibitors alone.