Abstract
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.
Highlights
Cancer is defined as a disease of chronic inflammation
As receptor tyrosine kinase (RTK) upregulation drives the activation of mitogen-activated protein kinase (MAPK)-independent survival pathways, RTKshigh and MITFlow melanoma cells are resistant to MAPK inhibition, and it has been proposed that dedifferentiated and slow cycling melanoma cells may constitute a reservoir of cells from which resistant cells can emerge through the acquisition of additional mutations [33,46,47]
Cancer associated fibroblasts (CAFs) are known to localize to the leading edge of the invasive front and to remodel the extracellular matrix (ECM) in order to create tracks for the collective migration of cancer cells. This process is triggered by Oncostatin, a member of the interleukin 6 (IL-6) family that signals through the receptor subunit GP130-IL6ST and janus kinase 1 (JAK1) to generate Rho-dependent actomyosin contractility [77]
Summary
Cancer is defined as a disease of chronic inflammation. Fibrosis, a pathological feature of chronic inflammatory diseases, is known to predispose and enhance cancer initiation and progression, mimicking the mechanism of a “non-healing wound” [1]. In addition to cancer-induced chronic inflammation, a fibrotic-like microenvironment can be induced by anti-cancer treatments, such as traditional chemotherapies and radiotherapy [2]. A deregulated process of wound healing driven by myofibroblasts leads to the accumulation of scar tissue and to tissue fibrosis [3]. Cancer-associated fibroblasts [4], a stromal cell population of the tumor microenvironment with tumorigenic properties, behave in a way close to myofibroblasts in the process of wound healing [5]. In melanoma, local stromal fibroblasts but cancer cells themselves can acquire a myofibroblast-like phenotype characterized by a contractile phenotype [12]. We describe the main functional properties of myofibroblasts in wound healing and fibrosis and how melanoma cells can highjack some of them under BRAF and MEK inhibitor treatment. We discuss potential therapeutic options to target this fibrotic-like response in the context of melanoma resistance
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