The past 5 years have witnessed a dizzying pace of progress for the treatment of melanoma, with nearly a dozen new molecularly targeted and immune-based therapies transforming the disease from an aggressively lethal malignancy into one that is readily treatable.
Yet, many patients continue to succumb to disease since only some respond to the available drugs and those who do respond often develop resistance. To carve out a path forward requires a broader picture of melanoma development and progression.
Next-generation sequencing technology is providing greater insight and has uncovered new and unexpected players in melanoma. It has also revealed one of the highest rates of somatic mutations among all types of cancer, presenting a significant challenge to pick out the true drivers of this disease. Tackling this challenge will likely have important implications for prognosis and therapy in the future.
Expanding Treatment Options
Melanoma is a malignant tumor of the skin pigment–producing melanocytes. As researchers have begun to characterize melanoma at the molecular level, it has become clear that the mitogen- activated protein kinase (MAPK) pathway is a key mediator of growth and proliferation.
The BRAF kinase, a MAPK pathway component that is mutated in around half of all patients with melanoma, offered an obvious target. The development of small-molecule inhibitors of this protein culminated in FDA approval of vemurafenib (Zelboraf) in 2011 and dabrafenib (Tafinlar) in 2013.
Meanwhile, attempts to target other components of the MAPK pathway led to approval of inhibitors of the kinase immediately downstream of BRAF, mitogen-activated protein kinase kinase (MEK). Melanoma also has been the poster child for immunotherapies that boost the antitumor immune response, particularly immune checkpoint inhibitors. The cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor ipilimumab (Yervoy) launched the field and was followed by drugs targeting programmed cell death-1 (PD-1) receptor and its ligands PD-L1 and PD-L2. Pembrolizumab (Keytruda) and nivolumab (Opdivo) both received regulatory approval in 2014, and were joined by the first immune combination therapy of ipilimumab plus nivolumab in 2015.
UV Damage Leaves Characteristic Marks
For the most part, comprehensive genome-wide studies have focused on the most common and aggressive form of melanoma, cutaneous melanoma. Numerous whole-genome and whole-exome studies have been performed, and melanoma was also among the tumor types chosen by The Cancer Genome Atlas (TCGA) as part of its sequencing efforts.
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3. Harbour JW, Onken MD, Roberson ED, et al. Science. 2010;330(6009):1410-1413.
Ultraviolet radiation (UVR) is the major environmental risk factor for cutaneous melanoma and this has been reflected in the genomic profiles uncovered in sequencing studies. The vast majority of tumors display a genomic signature indicative of damage caused by UVR, dominated by cytosine-to-thymine (C>T) nucleotide substitutions and CC>TT mutations. In the TCGA’s study, 76% of primary and 84% of metastatic tumors displayed a UVR signature of >60% C>T transitions and >5% CC>TT mutations.
Genome sequencing studies also revealed the strikingly high number of somatic mutations in melanoma. According to the TCGA, there were 16.8 mutations/Mb, the highest reported for any cancer evaluated through the program. The high mutational load is thought to result from UV radiation exposure and the high prevalence of C>T substitutions. Furthermore, it’s thought that this is what makes melanomas so immunogenic and thus uniquely susceptible to immunotherapies.
Unveiling Key Players Old and New
Predictably, the standout finding has been the identification of BRAF
mutations across all studies, in 50%-60% of cutaneous melanomas. The most common type of BRAF
mutation, in up to 90% of cases, results in the substitution of a valine at position 600 to a glutamic acid (V600E).BRAF
mutations are associated with increased sensitivity to BRAF- and MEK-targeted therapies, and determination of BRAF
mutation status is a prerequisite for treatment with these drugs. Currently, BRAF and MEK inhibitors are only approved for use in advanced-stage melanomas, but mounting evidence suggests that BRAF
mutations can be identified in earlier stages of melanoma.
Numerous other driver genes have now been identified in melanoma, including other components of the MAPK pathway. After BRAF
, the most frequently somatically altered gene in melanoma is NRAS
, a member of the RAS GTPase family of proteins, which sits upstream of BRAF in the MAPK pathway, recruiting it to the cell membrane to be activated.