The melanoma revolution: from UV carcinogenesis to a new era in therapeutics

Abstract

Melanoma, the deadliest form of skin cancer, is an aggressive disease that is rising in incidence. Although melanoma is a historically treatment-resistant malignancy, in recent years unprecedented breakthroughs in targeted therapies and immunotherapies have revolutionized the standard of care for patients with advanced disease. Here, we provide an overview of recent developments in our understanding of melanoma risk factors, genomics, and molecular pathogenesis and how these insights have driven advances in melanoma treatment. In addition, we review benefits and limitations of current therapies and look ahead to continued progress in melanoma prevention and therapy. Remarkable achievements in the field have already produced a paradigm shift in melanoma treatment: Metastatic melanoma, once considered incurable, can now be treated with potentially curative rather than palliative intent.

Fig. 1

Clinical images of melanomas. Subtypes of melanoma include superficial spreading melanoma (A), amelanotic melanoma (B), nodular melanoma (C), acral lentiginous melanoma (D), and uveal melanoma (E). Images courtesy of H. Tsao, C.H. Won, and I. Kim.

Fig. 2

Signaling pathways in melanoma. MAPK signaling promotes cell growth and survival and is constitutively active in most melanomas. RAS family members are activated by RTKs and signal through effector proteins including PI3K, RAF kinases, and Ral-GEFs. Oncogenic BRAF and NRAS are found in 40–60% and 10–30% of melanomas, respectively. c-KIT signaling is essential for melanocyte development and is associated with melanomas arising on acral, mucosal, and chronically sun-damaged skin. Mutations in GNAQ and GNA11, two G protein α-subunits involved in MAPK signaling, are the dominant genetic lesions in uveal melanomas. MITF, the master transcriptional regulator in melanocytes and lineage-specific oncogene, is expressed in response to MC1R signaling. Loss-of-function variants of MC1R are associated with the red hair/fair skin phenotype and increased melanoma susceptibility. Known melanoma oncogenes and tumor suppressors are labeled in red. Dotted lines represent omitted pathway components.

Fig. 3

Timeline of FDA regulatory approval for metastatic melanoma. Between 1976 and 2011, dacarbazine chemotherapy (1976) and high-dose IL-2 (1998) were the only approved agents for the treatment of advanced melanoma. The number of approved agents more than tripled in the last three years with the approvals of ipilimumab (anti-CTLA-4 antibody) and vemurafenib (BRAF inhibitor) in 2011, dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) in 2013, and pembrolizumab (anti-PD-1 antibody) in 2014. FDA approval of nivolumab (anti-PD-1 antibody) is anticipated in the near future. Targeted therapies labeled in green; immunotherapies labeled in purple.

Fig. 4

Cutaneous response to UVR. Tanning involves p53 activation in keratinocytes in response to UVR-induced DNA damage, leading to p53-mediated upregulation of proopiomelanocortin (POMC). Post-translational cleavage of POMC produces β-endorphin and α-MSH. Secreted α-MSH stimulates MC1R on adjacent melanocytes, resulting in melanin synthesis and eventual transfer of melanin-containing vesicles (melanosomes) to keratinocytes. Chronic UVR results in elevated circulating β-endorphin levels, leading to analgesia and physical dependence.