Other targets and oncogenes

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

The clinical development of combinatorial approaches utilizing selective inhibitors of the V600-mutant BRAF protein is progressing rapidly as described. As these inhibitors may increase the growth of melanomas with a wild-type BRAF gene, these approaches are not likely to be applicable to patients without activating BRAF mutations. The non-V600 BRAF mutant population includes more than half of cutaneous melanoma patients, and even higher percentages of patients with other types of melanoma (i.e. acral, mucosal, and uveal). Thus, combinatorial strategies are also being developed for other targets that have been identified in this disease.

Activating mutations of NRAS are the second most common oncogenic somatic mutation detected in cutaneous melanomas. In addition to their prevalence, studies in both earlyand late-stage melanoma patients support that melanoma patients with NRAS mutations have a worse prognosis than patients with activating BRAF mutations or wild-type BRAF and NRAS [17, 48]. Thus, the development of effective therapies for this subset of patients is a high priority. Direct targeting of RAS proteins is difficult to achieve due to the high affinity of the mutant RAS for GTP. Targeting RAS activation by inhibiting post-translational modifications that are required for its activation has been attempted in multiple tumor types, but to date this strategy has failed to produce clinical benefit [123]. As targeting RAS itself is challenging, multiple strategies have been developed to inhibit the multiple effector pathways that mediate its oncogenic effects [124, 125]. As activation of the RAS-RAF-MEK-ERK signaling cascade appears to be central to its effects, MEK inhibitors have been explored extensively as single agents and in combinations. A clinical trial with the MEK inhibitor binimetinib (MEK162) reported that clinical responses were observed in 28% of patients with activating NRAS mutations, while an additional 46% achieved disease stabilization [126]. However, the duration of disease control was quite short, and the overall median PFS was only 3.65 months. Multiple preclinical studies support that combined inhibition of MEK with targets in the PI3K-AKT pathway may be an effective strategy in RAS-mutant cancers, including melanoma [127–129]. Multiple clinical trials are currently ongoing testing this strategy. Recently, a GEMM of doxycycline-inducible mutant NRAS-expressing melanoma was used to compare the effects of MEK inhibitor treatment to complete extinction of NRAS signaling (doxycycline withdrawal) [130]. Surprisingly, the experiments demonstrated that MEK inhibition had similar efficacy to NRAS withdrawal in terms of apoptosis induction, but it was inferior at blocking cellular proliferation. Pathway analysis identified the cell cycle regulator CDK4 as a targetable node that correlated with this difference, and combined treatment with small molecule CDK4 inhibitors induced complete tumor regression in both the GEMM and in xenografts of NRAS-mutant human melanoma cells. Clinical trials will test the safety and efficacy of this strategy in patients. CDK4 is also an attractive combinatorial target in melanomas with activating BRAF mutations, as these tumors can have loss of P16, as well as activation of CDK4 (mutation or amplification) [42, 43]. Both loss of P16 and increased gene copy number of cyclin D1, another cell cycle regulator, correlated with shorter PFS in patients treated with dabrafenib in phase I/II clinical trials, providing further support for the clinical testing of this approach [108].

Activating mutations in GNaQ or GNa11 are present in the majority of uveal melanomas, particularly those that have metastasized [36]. The most common mutations in these genes occur at the residue that is analogous to the Q61 residue of RAS proteins. Thus, similar to RAS, therapeutic development is generally focusing on effector pathways that are downstream of these mutations [35]. The initial characterization of GNaQ mutations demonstrated that this event activates signaling through the RAS-RAF-MEK-ERK signaling pathway. Preliminary results suggest that MEK inhibitors may be clinically effective in these patients. However, in vitro studies demonstrated that the efficacy of MEK inhibition may be compromised by compensatory activation of the PI3K-AKT pathway [131]. Combined treatment with MEK and PI3K inhibitors induced synergistic growth inhibition and apoptosis, supporting the rationale for testing of this combination in uveal melanoma. Testing is also ongoing with other effectors, including inhibitors of protein kinase C (PKC).

Alternatively, strategies to target growth factors and/or their receptors that are critical to growth in the liver, which is the most common metastatic site for uveal melanoma, are being evaluated clinically and preclinically [132].

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