Grimm, Johannes and Hufnagel, Anita and Wobser, Marion and Borst, Andreas and Haferkamp, Sebastian and Houben, Roland and Meierjohann, Svenja (2018) BRAF inhibition causes resilience of melanoma cell lines by inducing the secretion of FGF1. ONCOGENESIS, 7: 71. ISSN 2157-9024,
Full text not available from this repository. (Request a copy)Abstract
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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | POTENT ANTITUMOR-ACTIVITY; ACQUIRED-RESISTANCE; UP-REGULATION; RAF INHIBITORS; MAPK PATHWAY; KAPPA-B; GROWTH; RECEPTORS; THERAPY; PLX4032; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Dermatologie und Venerologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 12 Dec 2019 14:08 |
| Last Modified: | 12 Dec 2019 14:08 |
| URI: | https://pred.uni-regensburg.de/id/eprint/13842 |
Actions (login required)
 |
View Item |
