Refine
Has Fulltext
- yes (15)
Is part of the Bibliography
- yes (15)
Year of publication
Document Type
- Journal article (15)
Language
- English (15)
Keywords
- melanoma (5)
- NRF2 (4)
- ATF4 (2)
- KEAP1 (2)
- Melanoma (2)
- angiogenesis (2)
- machine learning (2)
- BRAF (1)
- Biologie (1)
- CD274 (1)
- CHAC1 (1)
- COX2 expression (1)
- EGF (1)
- EGFR (1)
- Egfr (1)
- Epidermaler Wachstumsfaktor-Rezeptor (1)
- GSH (1)
- HNSC (1)
- JAK2 (1)
- MITF-low (1)
- Medizin (1)
- NF-κB (1)
- NFE2L2 (1)
- NSCLC (1)
- Nrf2 (1)
- PD-L1 (1)
- PI3K (1)
- RAS (1)
- SLC7A11 (1)
- TGF-alpha (1)
- TP53 (1)
- chemotherapy resistance (1)
- crosstalk (1)
- epidermal growth factor receptor (1)
- hypoxia-independent (1)
- immune evasion (1)
- immune infiltration (1)
- integrated stress response (1)
- kidney cancer (1)
- mRNA (1)
- mTOR (1)
- melanoma malignancy (1)
- miRNA (1)
- mitochondrial DNA (1)
- mtDNA (1)
- oxidative stress (1)
- p53 (1)
- pan-RCC (1)
- reactive oxygen species (1)
- senescence (1)
- teleost fishes (1)
- thiol starvation (1)
- transcriptome (1)
- tumor (1)
- tumor microenvironment (1)
Institute
- Theodor-Boveri-Institut für Biowissenschaften (11)
- Pathologisches Institut (6)
- Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie (5)
- Comprehensive Cancer Center Mainfranken (4)
- Rudolf-Virchow-Zentrum (4)
- Medizinische Klinik und Poliklinik II (3)
- Center for Computational and Theoretical Biology (2)
- Urologische Klinik und Poliklinik (2)
- Klinik und Poliklinik für Nuklearmedizin (1)
- Physiologisches Institut (1)
Schriftenreihe
Approximately half of all melanoma patients harbour activating mutations in the serine/threonine kinase BRAF. This is the basis for one of the main treatment strategies for this tumor type, the targeted therapy with BRAF and MEK inhibitors. While the initial responsiveness to these drugs is high, resistance develops after several months, frequently at sites of the previously responding tumor. This indicates that tumor response is incomplete and that a certain tumor fraction survives even in drug-sensitive patients, e.g., in a therapy-induced senescence-like state. Here, we show in several melanoma cell lines that BRAF inhibition induces a secretome with stimulating effect on fibroblasts and naive melanoma cells. Several senescence-associated factors were found to be transcribed and secreted in response to BRAF or MEK inhibition, among them members of the fibroblast growth factor family. We identified the growth factor FGF1 as mediator of resilience towards BRAF inhibition, which limits the pro-apoptotic effects of the drug and activates fibroblasts to secrete HGF. FGF1 regulation was mediated by the PI3K pathway and by FRA1, a direct target gene of the MAPK pathway. When FGFR inhibitors were applied in parallel to BRAF inhibitors, resilience was broken, thus providing a rationale for combined therapeutical application.