Cell death-based treatments of melanoma:conventional treatments and new therapeutic strategies

Abstract

The incidence of malignant melanoma has continued to rise during the past decades. However, in the last few years, treatment protocols have significantly been improved thanks to a better understanding of the key oncogenes and signaling pathways involved in its pathogenesis and progression. Anticancer therapy would either kill tumor cells by triggering apoptosis or permanently arrest them in the G1 phase of the cell cycle. Unfortunately, melanoma is often refractory to commonly used anticancer drugs. More recently, however, some new anticancer strategies have been developed that are “external” to cancer cells, for example stimulating the immune system’s response or inhibiting angiogenesis. In fact, the increasing knowledge of melanoma pathogenetic mechanisms, in particular the discovery of genetic mutations activating specific oncogenes, stimulated the development of molecularly targeted therapies, a form of treatment in which a drug (chemical or biological) is developed with the goal of exclusively destroying cancer cells by interfering with specific molecules that drive growth and spreading of the tumor. Again, after the initial exciting results associated with targeted therapy, tumor resistance and/or relapse of the melanoma lesion have been observed. Hence, very recently, new therapeutic strategies based on the modulation of the immune system function have been developed. Since cancer cells are known to be capable of evading immune-mediated surveillance, i.e., to block the immune system cell activity, a series of molecular strategies, including monoclonal antibodies, have been developed in order to “release the brakes” on the immune system igniting immune reactivation and hindering metastatic melanoma cell growth. In this review we analyze the various biological strategies underlying conventional chemotherapy as well as the most recently developed targeted therapies and immunotherapies, pointing at the molecular mechanisms of cell injury and death engaged by the different classes of therapeutic agents.

Genome‐wide screening identifies novel genes and biological processes implicated in cisplatin resistance

“…Melanoma is the most aggressive skin cancer and notoriously resistant to chemotherapeutic agents, including cisplatin (4). Marked improvements in melanoma treatments, especially those with small-molecule targeted drugs and immunotherapies, have been achieved over the past decade.…”

Repurposing the serotonin agonist Tegaserod as an anticancer agent in melanoma: molecular mechanisms and clinical implications

“…The current repertoire of clinically approved treatment options in melanoma encompasses agents that inhibit proliferation and induce cell death [44]. This includes targeted inhibitors of the BRAF pathway and checkpoint inhibitors.…”

“…Error bars in the all experiments indicate SEM. *P < 0.05 as determined by a determined by a Student's t-test (unpaired, 2 tailed) or and log-rank test for analysis of Kaplan Meier survival curves the checkpoint inhibitors cause immunogenic cell death through lytic and apoptotic cell death mediated by activated CD8 + T and NK cells respectively [6,44].…”

“…Furthermore, as the compound synergized with Vemurafenib and other kinase inhibitors currently used in melanoma patients with late-stage disease, this is likely a favorable point of clinical entry especially since most patients eventually develop resistance to Vemurafenib and other kinase inhibitors [7,47]. Furthermore, as the BRAF WT cohort of patients are a diverse group, treatment options are much less clear cut [44,58] although immunotherapies, as with BRAF V600E melanoma are a promising albeit costly treatment approach [59]. Currently there are a lot of different combinations in clinical trials using MEK in combination with inhibitors of the PI3K/ AKT/mTOR axis [58] (NCT01941927, NCT01363232, NCT01337765).…”

β‐Adrenoceptors as drug targets in melanoma: novel preclinical evidence for a role of β3‐adrenoceptors

“…More recently, targeting the immune system with the use of checkpoint inhibitors is emerging as an elective option for melanoma treatment (Schadendorf et al ., ). However, after the initial results associated with targeted therapies, tumour resistance or relapse of the melanoma lesion has been observed (Mattia et al ., ) suggesting the need for additional therapies to treat melanoma.…”