BRAF targets in melanoma. Biological mechanisms, resistance, and drug discovery. Cancer drug discovery and development. Volume 82. Ed. Ryan J. Sullivan. Springer (2015)

The incidence of melanoma continues to increase at a rate of 2–5% per year with an estimated 76,250 new cases diagnosed in 2012 [120]. The magnitude of this disease is further exacerbated by the fact that although melanoma represents 5% of skin cancers, it is the cause of 80% of skin cancer-related deaths [93]. The majority (70%) of newly diagnosed patients present with thin melanoma (= 1 mm) and the prognosis for patients with only local disease is excellent [87, 46, 7]. However, approximately 4% of patients present with distant metastatic melanoma and a subset of patients with localized melanoma eventually develop systemic metastases and have significantly worsened survival [7, 32].

In the past, systemic treatments for distant metastatic melanoma were generally ineffective with response rates of 5–20% for chemotherapy, and the prognosis of patients with distant disease is dismal with median survival rates of less than 1 year [48, 7]. However, in 2011 a turning point was achieved in the fight against metastatic melanoma with the FDA approval of both anti-CTLA-4 antibody immunotherapy and BRAF targeted therapy. In patients treated with the anti-CTLA-4 antibody ipilimumab, an objective response was seen in 10.9% of patients and median overall survival was significantly increased to 10 months [59]. Even more impressive were the results seen with targeted therapy using vemurafenib in BRAF mutated melanoma. In the pivotal phase III trial, 48% of treated patients with metastatic melanoma had an objective response as determined in an interim analysis, although the vast majority of patients had some decrease in tumor size, and the median progression-free survival was significantly extended to 5.3 months compared with 1.6 months for patients treated with dacarbazine [26]. Despite the impressive results and dramatic response rates seen after vemurafenib therapy, nearly all of these patients eventually developed recurrent disease. The mechanisms by which melanomas acquire resistance to BRAF inhibitors is an active area of research, and it is now apparent that combination therapy based upon a BRAF inhibitor backbone is the therapeutic future for disseminated disease [124, 127, 122, 123]. At this juncture, the cellular pathways that need to be targeted in conjunction with mutant BRAF are still being determined.

Acquisition of a BRAF mutation is believed to be an early event in melanoma development as evidenced by the fact that over 80% of nevi harbor a BRAF mutation [104, 75]. As a single hit, oncogenic BRAF drives melanocytes into senescence and it is known that additional genetic insults are required for melanomagenesis. Among the hits identified so far that contribute to melanoma development are alterations in regulatory pathways for p53 and the cell cycle [28, 33; 16, 63, 135]. In this chapter, we will review the important alterations in the cell cycle and p53 regulatory pathways implicated in melanoma initiation and progression and will discuss the potential for targeting these alterations in combination with oncogenic BRAF.

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