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.
Highlights
Melanoma cells carrying the mutated BRAF oncogene become addicted to its constitutive activity, which can be therapeutically targeted by kinase inhibitors, such as vemurafenib or its analog PLX-4720, achieving cytostatic and cytotoxic effects [1,2]
VEGF-dependent neuropilin signaling has been reported to play a relevant role in cancer; we have previously shown that VEGF is unlikely to be implicated in establishing NRP1-dependent melanoma resistance to BRAF inhibitors [7]
We have previously shown that melanoma cells resistant to BRAF-targeted therapy acquire NRP1 neo-expression, driving an intrinsic mechanism of drug refractoriness [7]
Summary
Melanoma cells carrying the mutated BRAF oncogene become addicted to its constitutive activity, which can be therapeutically targeted by kinase inhibitors, such as vemurafenib or its analog PLX-4720, achieving cytostatic and cytotoxic effects [1,2]. We have previously demonstrated that melanoma cells treated with BRAF inhibitors upregulate the cell surface receptor Neuropilin-1 (NRP1), which elicits an EGFR-dependent mechanism of adaptive resistance to therapy [7]. NRP1 is a multifunctional receptor interacting with a range of extracellular ligands [12], which might represent relevant triggers of NRP1-dependent tumor malignancy and molecular targets for restoring drug sensitivity. In this respect, VEGF-dependent neuropilin signaling has been reported to play a relevant role in cancer; we have previously shown that VEGF is unlikely to be implicated in establishing NRP1-dependent melanoma resistance to BRAF inhibitors [7]
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