Dual Inhibition of MAPK and JAK2/STAT3 Pathways Is Critical for the Treatment of BRAF Mutant Melanoma.

BRAF and MEK inhibitors significantly prolong progression-free survival in patients with BRAF mutant melanoma. However, most patients quickly develop drug resistance. The mechanism of drug resistance is complicated and remains to be further explored. Here, we found that inhibition of the MAPK pathway activates the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway, whereas JAK2 inhibitors that inhibit the JAK2/STAT3 pathway activate the MAPK pathway, suggesting a crosstalk between these two pathways in BRAF mutant melanoma cells. Reactivation of the MAPK pathway occurs in most drug-resistant patients with BRAF mutations. Therefore, dual inhibition of the MAPK and JAK2/STAT3 pathways is critical for the treatment of BRAF mutant melanoma. However, we found that the combination of BRAF, MEK inhibitors, and JAK2 or STAT3 inhibitors could not simultaneously inhibit the MAPK and JAK2/STAT3 pathways in BRAF mutant melanoma cells. Subsequently, we found that a combination of all three MAPK pathway inhibitors-BRAF, MEK, and ERK inhibitors-with JAK2 or STAT3 inhibitors can dually inhibit the MAPK and JAK2/STAT3 pathways, showing a significant inhibition of the growth of BRAF mutant melanoma cells compared with either treatment alone. Therefore, dual inhibition of MAPK and JAK2/STAT3 pathways may be a novel strategy for the treatment of BRAF mutant tumors.