Abstract
Malignant melanoma is the most aggressive form of skin cancer and has a very low survival rate. Over 50% of melanomas harbor various BRAF mutations with the most common being the V600E. BRAFV600E mutation that causes constitutive activation of the MAPK pathway leading to drug-, immune-resistance, apoptosis evasion, proliferation, survival, and metastasis of melanomas. The ATP competitive BRAFV600E selective inhibitor, vemurafenib, has shown dramatic success in clinical trials; promoting tumor regression and an increase in overall survival of patients with metastatic melanoma. Regrettably, vemurafenib-resistance develops over an average of six months, which renders melanomas resistant to other therapeutic strategies. Elucidation of the underlying mechanism(s) of acquisition of vemurafenib-resistance and design of novel approaches to override resistance is the subject of intense clinical and basic research. In this review, we summarize recent developments in therapeutic approaches and clinical investigations on melanomas with BRAFV600E mutation to establish a new platform for the treatment of melanoma.
Highlights
Malignant melanoma is the most aggressive form of skin cancer and has a very low survival rate
Adoptive T-cell therapy (ACT) isolates, expands, and infuses tumor-infiltrating lymphocytes (TIL) in patients [27,28]. These lymphocytes are transduced with high affinity T cell receptors against specific tumor antigens with a clinical response rate over 50%, which reveals it as a successful treatment against metastatic melanoma [29]
The eventual relapse and bypass of the melanoma cells treated with vemurafenib is due to the resistance mechanisms that progress over time
Summary
Melanoma has a 10–15% five-year survival rate and is considered as the most aggressive form of skin cancer. Various treatments are available but do not always extend survival and are usually associated with toxicity These modalities include surgery, radiation therapy, chemotherapy, and immunotherapy [6]. IFN-alpha 2β induces apoptosis in melanoma lines via a caspase-dependent manner [16] It was the first agent with significant survival benefits in clinical trials with a survival rate of 3.82 years [17]. Adoptive T-cell therapy (ACT) isolates, expands, and infuses tumor-infiltrating lymphocytes (TIL) in patients [27,28]. These lymphocytes are transduced with high affinity T cell receptors against specific tumor antigens with a clinical response rate over 50%, which reveals it as a successful treatment against metastatic melanoma [29]. TIL therapy is effectively induced in more than 60% of all patients and has higher response rates than ipilimimab or IL-2 [14,30]
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