HER3-Receptor-Mediated STAT3 Activation Plays a Central Role in Adaptive Resistance toward Vemurafenib in Melanoma

SIMPLE SUMMARY: The major obstacle for the long-term success of targeted therapies in melanoma is the occurrence of resistance. Here, we present a new mechanism of targeted therapy resistance in melanoma where the treatment with the BRAF inhibitor vemurafenib causes an increased activation of HER3 via shed ligands. This is followed by an activation of STAT3 via HER3 and results in the expression of the STAT3 target gene SOX2. Pharmacological inhibition of HERs sensitizes melanoma cells toward vemurafenib treatment. Thus, blocking HER family members and especially HER3 in addition to targeted therapy treatment might prevent the occurrence of resistance. ABSTRACT: Melanoma is an aggressive form of skin cancer that is often characterized by activating mutations in the Mitogen-Activated Protein (MAP) kinase pathway, causing hyperproliferation of the cancer cells. Thus, inhibitors targeting this pathway were developed. These inhibitors are initially very effective, but the occurrence of resistance eventually leads to a failure of the therapy and is the major obstacle for clinical success. Therefore, investigating the mechanisms causing resistance and discovering ways to overcome them is essential for the success of therapy. Here, we observed that treatment of melanoma cells with the B-Raf Proto-Oncogene, Serine/Threonine Kinase (BRAF) inhibitor vemurafenib caused an increased cell surface expression and activation of human epidermal growth factor receptor 3 (HER3) by shed ligands. HER3 promoted the activation of signal transducer and activator of transcription 3 (STAT3) resulting in upregulation of the STAT3 target gene SRY-Box Transcription Factor 2 (SOX2) and survival of the cancer cells. Pharmacological blocking of HER led to a diminished STAT3 activation and increased sensitivity toward vemurafenib. Moreover, HER blocking sensitized vemurafenib-resistant cells to drug treatment. We conclude that the inhibition of the STAT3 upstream regulator HER might help to overcome melanoma therapy resistance toward targeted therapies.