**12. BRAF inhibitors**

treatment or in combination therapy for melanoma or other malignancies, such as hepatocellular carcinoma, metastatic liver tumors, advanced non-central nervous system tumors, breast cancer, pancreatic cancer, Merkel cell carcinoma, head and neck cancer, sarcoma, lymphomas. In a Phase I study, T-VEC has been combined with ipilimumab or pembrolizumab, with promising results without overlapping toxicities. The results of larger studies are awaited to

Selected somatic changes such as BRAF mutations have been described, and then applied to the targeted treatments. BRAF gene is located in chromosomal region 7q34; it consists of 18 exons and transcribed mRNA length was 2478 bp. Targeted therapy is based on the knowledge of the molecular biology of the gene encoding the BRAF kinase, belonging to the RAF kinase family. It is a serine/threonine kinase that takes part in the Mitogen Activated

**Figure 2.** Mechanism of action of kinase inhibitors. This figure shows a schema of signaling pathways triggered by binding of growth factors to tyrosine kinase receptor that triggers RAS, RAF, MEK and ERK pathways leading to cell growth and proliferation. Mutations in BRAF (V600E) can lead to accelerated cell growth and cancer formation of melanoma cells. Inhibition of mutant BRAF by dabrafenib, vemurafenib in the melanoma cells shuts down the signaling pathway causing tumor regression following cell apoptosis, tumor antigen expression and decreased release of cytokines and VEGF. MEK is a member of the MAPK signaling cascade that is activated in melanoma. Inhibition of MEK by selumetinib, trametinib blocks cell proliferation and induces apoptosis (controlled cell death). MAPK, mitogen activated protein kinase; ERK, extracellular signal-regulated kinase; VEGF, vascular endothelial growth factor.

further delineate T-VEC's place with combination therapy [51].

118 Human Skin Cancers - Pathways, Mechanisms, Targets and Treatments

**11. Targeted therapy**

*Vemurafenib* (Zelboraf® tablets, Roche) is the first selective inhibitor of BRAF developed by Plexxikon and approved by FDA in 2011 (**Figure 3**). It leads to a rapid, and sometimes the complete remission of the disease in patients with a mutated BRAF V600E. A clinical study on 675 respondents treated with vemurafenib, 960 mg twice daily, demonstrated survival of 6 months in 84% of patients versus 64% of patients treated with dacarbazine. Despite significant benefit in the treatment, there were new challenges identified – the development of resistance to reactivation of MAPK signaling and growth of keratoacanthomas and squamous cells. The most common adverse events were headache, joint pain, fatigue, skin hyperkeratosis and 6% of the patients experienced a squamous cell carcinoma [56].

*Dabrafenib* (Tafinlar® capsules), developed by GlaxoSmithKline (**Figure 3**), selectively inhibits BRAF ValGlu [57]. It is a thiazole derivative, which binds to the ATP binding site of BRAF kinase. It has a shorter half-life than vemurafenib (5.2 h versus 50 h). In 2009, first clinical studies in

**Figure 3.** Chemical structures of vemurafenib, dabrafenib, trametinib, and selumetinib.

Phase I/II began. In Phase III clinical trials, the dosing regimen was 150 mg of dabrafenib twice daily, which significantly extended the survival to 5.1 months versus 2.7 months with dacarbazine. Hyperkeratosis, headache and joint pain, fatigue, heartburn have been reported as adverse events [24].

*Cobimetinib* (Cotellic™) was granted FDA approval on November 10, 2015 in combination with vemurafenib (BRAF inhibitor) for the treatment of patients with metastatic melanoma. The approval was based on the effectiveness of cobimetinib plus vemurafenib in a randomized Phase III clinical trial of 495 patients whose tumors had specific mutations in the BRAF gene and who were not candidates for surgery. Patients who received vemurafenib plus cobimetinib had a median progression-free of 12.3 months, compared with 7.2 months in patients who received vemurafenib plus placebo. At 17 months after initiating treatment, about 65% of patients who received the two-drug combination were still alive, compared with 50% of those

Possibilities for the Therapy of Melanoma: Current Knowledge and Future Directions

http://dx.doi.org/10.5772/intechopen.70368

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NRAS-mutant melanoma is a common subtype of this disease with a poor prognosis. NRAS is a low-molecular plasma-membrane–associated GTP-binding protein that constitutively activates intracellular signaling through a variety of pathways, most notably the RAS–RAF-MAPK and PI3K-AKT pathways. NRAS mutations activate MAPK signaling to a similar degree as BRAF mutations and rarely co-occur with mutations in the PI3K-AKT pathways, suggesting that mutant NRAS drives this pathway, too. NRAS mutation occurs in approximately 15–20% of melanomas, and it is the second most common oncogenic mutation in this

Farnesyltransferase inhibitors (FTIs) showed the most promising therapy targeting the NRAS mutant. FTIs alter post-translational NRAS modification to prevent insertion into the plasma membrane. A Phase II study of FTI R115777 was performed in advanced melanoma and its results showed no evidence of clinical activity despite potent inhibition of FTIs in tumor tissue. The effect of these inhibitors has resulted in a stage of toxicity involving myelosuppression, nausea/vomiting and anorexia. Gajewski et al. concluded that FTIs were originally developed as RAS inhibitors and they affect several signaling pathways with potential outcomes for outof-target toxicity. Multiple farnesylated proteins are involved in signal transduction in cancer. FTIs have been developed as a strategy to inhibit the function of these proteins. FTIs inhibit proliferation of melanoma cell lines. Farnesylated proteins are also important for T cell activa-

Alternative strategies for a directly targeted NRAS mutant include the use of either antisense oligonucleotides or small interfering RNAs (siRNAs, small interfering RNAs) on the mutant NRAS gene. However, this has proved to be technically very demanding and requires advances in siRNA technology before considering use under clinical conditions. Therefore, NRAS mutant melanomas are currently being treated by MEK inhibitors or by newer types of

The first agent to show robust activity specifically in NRAS-mutant melanoma has been an allosteric inhibitor of MEK1 and MEK2 *binimetinib* **(MEK162, ARRY-162)** developed by Array BioPharma. As part of a combined study of BRAF and NRAS mutant melanoma patients, 30 metastatic melanoma patients whose tumors harbored a NRAS mutation were enrolled

tion and measurement of effects on T cell function was also pursued [66].

immunotherapy that are not found in the presence of oncogenic mutation.

who received vemurafenib alone [64].

**14. NRAS inhibitors**

disease [65].
