HER3-receptor-mediated STAT3 activation plays a central role in adaptive resistance toward vemurafenib in melanoma
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 effecti...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article (Journal) |
| Language: | English |
| Published: |
14 December 2020
|
| In: |
Cancers
Year: 2020, Volume: 12, Issue: 12, Pages: 1-14 |
| ISSN: | 2072-6694 |
| DOI: | 10.3390/cancers12123761 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.3390/cancers12123761 Verlag, lizenzpflichtig, Volltext: https://www.mdpi.com/2072-6694/12/12/3761 
|
| Author Notes: | Laura Hüser, Marianthi-Maria Kokkaleniou, Karol Granados, Jennifer Dworacek, Aniello Federico, Marlene Vierthaler, Daniel Novak, Ihor Arkhypov, Thomas Hielscher, Viktor Umansky, Peter Altevogt and Jochen Utikal |
| Summary: | 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. |
|---|---|
| Item Description: | Gesehen am 17.02.2022 |
| Physical Description: | Online Resource |
| ISSN: | 2072-6694 |
| DOI: | 10.3390/cancers12123761 |