Current Advances in the Treatment of BRAF-Mutant Melanoma

Abstract

Melanoma is the most lethal form of skin cancer. Melanoma is usually curable with surgery if detected early, however, treatment options for patients with metastatic melanoma are limited and the five-year survival rate for metastatic melanoma had been 15–20% before the advent of immunotherapy. Treatment with immune checkpoint inhibitors has increased long-term survival outcomes in patients with advanced melanoma to as high as 50% although individual response can vary greatly. A mutation within the MAPK pathway leads to uncontrollable growth and ultimately develops into cancer. The most common driver mutation that leads to this characteristic overactivation in the MAPK pathway is the B-RAF mutation. Current combinations of BRAF and MEK inhibitors that have demonstrated improved patient outcomes include dabrafenib with trametinib, vemurafenib with cobimetinib or encorafenib with binimetinib. Treatment with BRAF and MEK inhibitors has met challenges as patient responses began to drop due to the development of resistance to these inhibitors which paved the way for development of immunotherapies and other small molecule inhibitor approaches to address this. Resistance to these inhibitors continues to push the need to expand our understanding of novel mechanisms of resistance associated with treatment therapies. This review focuses on the current landscape of how resistance occurs with the chronic use of BRAF and MEK inhibitors in BRAF-mutant melanoma and progress made in the fields of immunotherapies and other small molecules when used alone or in combination with BRAF and MEK inhibitors to delay or circumvent the onset of resistance for patients with stage III/IV BRAF mutant melanoma.

BRAF Inhibitors: Molecular Targeting and Immunomodulatory Actions

“…BRAF inhibitors have been shown to rapidly suppress melanoma growth and control the malignancy in a large proportion of patients [11,52,53]. Although BRAF inhibitors can induce good responses in many patients with BRAF-mutant melanoma, in some cases, a reduction in effectiveness can be observed after 7-8 months of therapy [32,54,55].…”

“…Although BRAF inhibitors can induce good responses in many patients with BRAF-mutant melanoma, in some cases, a reduction in effectiveness can be observed after 7-8 months of therapy [32,54,55]. Several mechanisms account for the reduction in tumour response to BRAF inhibitor therapy [52,53]. These include both primary (intrinsic) and secondary (acquired) mechanisms: primary applies to patients who do not respond to BRAF inhibitor therapy from the outset (approximately 15% of patients) [52]; whereas secondary mechanisms involve individuals who initially responded to BRAF inhibitor therapy, but subsequently relapsed [52].…”

“…Several mechanisms account for the reduction in tumour response to BRAF inhibitor therapy [52,53]. These include both primary (intrinsic) and secondary (acquired) mechanisms: primary applies to patients who do not respond to BRAF inhibitor therapy from the outset (approximately 15% of patients) [52]; whereas secondary mechanisms involve individuals who initially responded to BRAF inhibitor therapy, but subsequently relapsed [52]. Various pathways/mechanisms have been shown to potentially be involved in the development of acquired resistance [52]:…”

“…This led to an interest in immunotherapeutic agents to extend the therapeutic effect and induce long-acting anti-melanoma effects, and immune checkpoint inhibitors are another important treatment option for patients with advanced melanoma [11,16,52]. It has been reported that single-agent checkpoint inhibitors produced a clear clinical benefit over chemotherapy in metastatic melanoma, and these benefits appeared to be consistent across patient subgroups [66].…”

Ivermectin, a potential anticancer drug derived from an antiparasitic drug

“…Melanoma is the most common malignant skin tumor with a high mortality rate. Drugs targeting BRAF mutations such as vemurafenib, dabrafenib and PD-1 monoclonal antibodies, including pembrolizumab and nivolumab have greatly improved the prognosis of melanoma [ 71 , 72 ]. Gallardo treated melanoma cells with IVM and found that it could effectively inhibit melanoma activity [ 73 ].…”