Transcripts 202 and 205 of IL-6 confer resistance to Vemurafenib by reactivating the MAPK pathway in BRAF(V600E) mutant melanoma cells

BRAF mutations occur in approximately 50% of melanoma patients. The mutated BRAF kinase continuously activates the mitogen-activated protein kinase (MAPK) pathway to promote cell growth and proliferation. Vemurafenib as a specific BRAF inhibitor can significantly prolong progression-free survival in melanoma patients. However, most patients developed resistance to Vemurafenib after 6 months. The mechanism of drug resistance is not yet fully understood. In this study, we found that proteins secreted by drug-resistant cells protect sensitive cells from Vemurafenib. By RNA-seq, we compared differentially expressed genes between resistant and sensitive cells. We demonstrated that drug-resistant cells secrete more IL-6 protein than sensitive cells. For the first time, we found that IL-6 expressed by drug-resistant cells consists of the following transcripts: IL6-201, IL6-202 and IL6-205. We confirmed that it is the IL6-202 and IL6-205 transcripts that confer drug resistance to Vemurafenib by reactivating the MAPK pathway while IL6-201 is not responsible for the resistance in A375 melanoma cells. Neutralizing IL-6 significantly increased the sensitivity of drug-resistant cells to Vemurafenib. Overall, these results reveal a new mechanism of drug resistance in melanoma.