Abstract
Melanoma cells addicted to mutated BRAF oncogene activity can be targeted by specific kinase inhibitors until they develop resistance to therapy.We observed that the expression of Galectin-1 (Gal-1), a soluble ligand of Neuropilin-1 (NRP1), is upregulated in melanoma tumor samples and melanoma cells resistant to BRAF-targeted therapy. We then demonstrated that Gal-1 is a novel driver of resistance to BRAF inhibitors in melanoma and that its activity is linked to the concomitant upregulation of the NRP1 receptor observed in drug-resistant cells. Mechanistically, Gal-1 sustains increased expression of NRP1 and EGFR in drug-resistant melanoma cells. Moreover, consistent with its role as a NRP1 ligand, Gal-1 negatively controls p27 levels, a mechanism previously found to enable EGFR upregulation in cancer cells. Finally, the combined treatment with a Gal-1 inhibitor and a NRP1 blocking drug enabled resistant melanoma cell resensitization to BRAF-targeted therapy. In summary, we found that the activation of Galectin-1/NRP1 autocrine signaling is a new mechanism conferring independence from BRAF kinase activity to oncogene-addicted melanoma cells.
Original language | English |
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Article number | 2218 |
Pages (from-to) | 1-14 |
Number of pages | 14 |
Journal | Cancers |
Volume | 12 |
Issue number | 8 |
DOIs | |
Publication status | Published - Aug 2020 |
Keywords
- Autocrine signaling
- Braf
- Cancer therapy
- Cell signaling
- Egfr
- Galectin
- Melanoma
- Molecular biology
- Neuropilin
- Oncogenic signaling
ASJC Scopus subject areas
- Oncology
- Cancer Research