For instance, resistance to kinase inhibitors can be mediated by cues that are derived from paracrine secretion of tumors and the microenvironment, such as hepatocyte growth factor.495 The tumor microenvironment can also reshape fibroblasts which then promote extracellular matrix production and remodeling, leading to elevated integrin β1/FAK/Src signaling that rescues the antiproliferative effect of BRAF inhibitors in melanoma.496 However, many of these mechanisms were observed in preclinical murine cancer models, primarily of melanoma. This evidence concerns the gene SRC and melanoma.