FGD1 guanine nucleotide exchange factor drives secondary resistance to BRAF inhibition in melanoma.

FGD1 is an X-linked gene and acts as a guanine nucleotide exchange factor that activates guanosine triphosphatase Cdc42 and influences cell cycle progression, cell morphology, motility, and extracellular matrix degradation. In this study, we aim to understand FGD1 function in melanoma to better understand the correlation between poor survival and high FGD1 expression identified in The Cancer Genome Atlas messenger RNA data, especially in patients with BRAF mutations. FGD1 knockdown in BRAF V600E-mutated melanoma cell lines reduces cell proliferation and induces secondary resistance to BRAF inhibition, while increasing sensitivity to p21-activated kinase inhibition. Markedly, when FGD1 knockdown becomes ineffective, resistant cells not only restore endogenous FGD1 expression but also exhibit upregulation of epidermal growth factor receptor and phospho-p21-activated kinase, both known markers of BRAF inhibition resistance, highlighting a shift toward an adaptive resistance phenotype. Furthermore, we show that secondary resistance induced by prolonged exposure of melanoma cells to BRAF inhibitor is associated with reduced FGD1 levels. These findings highlight the importance of FGD1 in melanoma progression and the acquisition of secondary resistance, positioning the FGD1 -mediated signaling pathway as a putative therapeutic target.