Bad Neighborhood: Fibrotic Stroma as a New Player in Melanoma Resistance to Targeted Therapies

Current treatments for metastatic cutaneous melanoma include immunotherapies and drugs targeting key molecules of the mitogen-activated protein kinase (MAPK) pathway, which is often activated by BRAF driver mutations. Overall responses from patients with metastatic BRAF mutant melanoma are better with therapies combining BRAF and mitogen-activated protein kinase kinase (MEK) inhibitors. However, most patients that initially respond to therapies develop drug resistance within months. Acquired resistance to targeted therapies can be due to additional genetic alterations in melanoma cells and to non-genetic events frequently associated with transcriptional reprogramming and a dedifferentiated cell state. In this second scenario, it is possible to identify pro-fibrotic responses induced by targeted therapies that contribute to the alteration of the melanoma tumor microenvironment. A close interrelationship between chronic fibrosis and cancer has been established for several malignancies including breast and pancreatic cancers. In this context, the contribution of fibrosis to drug adaptation and therapy resistance in melanoma is rapidly emerging. In this review, we summarize recent evidence underlining the hallmarks of fibrotic diseases in drug-exposed and resistant melanoma, including increased remodeling of the extracellular matrix, enhanced actin cytoskeleton plasticity, high sensitivity to mechanical cues, and the establishment of an inflammatory microenvironment. We also discuss several potential therapeutic options for manipulating this fibrotic-like response to combat drug-resistant and invasive melanoma.