Autocrine Signaling of NRP1 Ligand Galectin-1 Elicits Resistance to BRAF-Targeted Therapy in Melanoma Cells.
Sabrina RizzolioSimona CorsoSilvia GiordanoLuca TamagnonePublished in: Cancers (2020)
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.
Keyphrases
- drug resistant
- wild type
- poor prognosis
- metastatic colorectal cancer
- multidrug resistant
- acinetobacter baumannii
- small cell lung cancer
- tyrosine kinase
- epidermal growth factor receptor
- induced apoptosis
- cell proliferation
- long non coding rna
- skin cancer
- binding protein
- signaling pathway
- stem cells
- mesenchymal stem cells
- bone marrow
- drug delivery
- combination therapy
- cell death
- basal cell carcinoma
- adverse drug