The most common cancers of the skin are squamous cell carcinomas (SCC) or basal cell carcinomas (BCC), which arise from keratinocytes, rarely metastasize and respond well to treatment. Although melanomas, which originate from melanocytes (pigment producing cells), are more rare (2% of all skin cancers), they are responsible for the majority of skin cancer related death.
The vast majority of cutaneous melanomas are characterized by a constitutive activation of the MAPK pathway, and around 90% of melanomas show activating mutations in either the NRAS or the BRAF gene (around 60%, most of them the BRAFV600E mutation). Furthermore, the PI3K and some of its associated pathways (mTOR, AKT, NFkB) are often increased in melanoma, and in addition to genetic alterations, non-genetic mechanisms (e.g. PTEN promoter methylation) account for elevated PI3K signaling. In recent years, much efforts in melanoma research aimed to elucidate resistance mechanisms to BRAF inhibitors, which replaced the only standard of care chemotherapeutic drug dacarbazine as first line therapy in BRAF mutant melanomas in 2011. The emerging picture is that therapy resistance comprises several distinct mechanisms: Reactivation of the MAPK pathway occurs due to genetic alterations, alternate splicing, and microenvironmental influences. Additionally, the activation of compensatory pathways such as the PI3K, mainly due to enhanced receptor tyrosin kinase signaling, is frequent. Additionally, activation of stress response pathways such as the ER stress response and/or activation of autophagy are known determinants of therapeutic responses. An important role of the tumor microenvironment has been identified, where stromal cells secrete growth factors (e.g. HGF) to stimulate PI3K activation in response to BRAF inhibition. Another feature of melanoma with important implication in the resistance to targeted therapies is its high degree of plasticity – that is changing the phenotype in response to environmental stimuli. As such, melanoma cells may switch from a drug responsive to a drug resistant state, which has been shown to correlate with a low MITF/AXL expression ratio. MITF low melanomas are also associated with more aggressive features including tumor-initiating potential and ability to metastasize.
Finally, melanomas are characterized by their high immunogenicity, probably due to the high mutational load and consequently increased abundance of tumor-associated antigens. As such, melanomas are highly susceptible to immune therapies, especially immune checkpoint inhibition with CTLA-4 and PD-1 monoclonal antibodies.
TICC Faculty who are involved in skin cancer research:
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