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Review
. 2021 Nov 22;13(22):5847.
doi: 10.3390/cancers13225847.

Melanoma Targeted Therapies beyond BRAF-Mutant Melanoma: Potential Druggable Mutations and Novel Treatment Approaches

Karam Khaddour  1   2 , Lucas Maahs  2 , Ana Maria Avila-Rodriguez  2 , Yazan Maamar  3 , Sami Samaan  4 , George Ansstas  1
Affiliations
Review

Melanoma Targeted Therapies beyond BRAF-Mutant Melanoma: Potential Druggable Mutations and Novel Treatment Approaches

Karam Khaddour et al. Cancers (Basel). .

Abstract

Melanomas exhibit the highest rate of somatic mutations among all different types of cancers (with the exception of BCC and SCC). The accumulation of a multimode of mutations in the driver oncogenes are responsible for the proliferative, invasive, and aggressive nature of melanomas. High-resolution and high-throughput technology has led to the identification of distinct mutational signatures and their downstream alterations in several key pathways that contribute to melanomagenesis. This has enabled the development of individualized treatments by targeting specific molecular alterations that are vital for cancer cell survival, which has resulted in improved outcomes in several cancers, including melanomas. To date, BRAF and MEK inhibitors remain the only approved targeted therapy with a high level of evidence in BRAFV600E/K mutant melanomas. The lack of approved precision drugs in melanomas, relative to other cancers, despite harboring one of the highest rates of somatic mutations, advocates for further research to unveil effective therapeutics. In this review, we will discuss potential druggable mutations and the ongoing research of novel individualized treatment approaches targeting non-BRAF mutations in melanomas.

Keywords: BRAF; DNA damage repair; MEK; NF1; NRAS; epigenetic; homologous recombination deficiency; melanoma; molecular alteration; precision oncology; targeted therapy; tumor suppressor gene.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Epidemiology and trends of melanomas. (A) Age-standardized rate of melanoma cases per 100,000 in 2018 in selected countries per GLOBOCAN statistics [3]; (B) the 2011 incidence distribution among different ethnicities in the US [4]; (C) estimated incidence of melanoma cases in the US between 1990–2021 according to the American Cancer Society Statistics [6]; (D) estimated melanoma annual deaths in the US between 1990–2021 according to the American Cancer Society Statistics [6]. GLOBOCAN: Global Cancer Observatory.
Figure 2
Figure 2
Major signaling pathways in melanomas. The most essential pathways in melanomagenesis are the MAPK pathway (in green) and the PI3K pathway (violet). The MAPK pathway is activated by receptor tyrosine kinase and G-protein-coupled receptors. This activates RAS proteins, which in turn activates MEK, and then ERK. ERK can then translocate to the nucleus and phosphorylate transcriptional factor substrates involved in cell survival. NF1 negatively regulates RAS proteins which inhibits downstream RAS signaling. The PI3K pathway can be activated by RAS or through the inactivation of PTEN. PI3K can activate several pathways (BAD, NF-kB) and AKT pathways, which in turn leads to phosphorylation of mTOR, which leads to increased cellular proliferation. The CDKN2A pathway is another essential network in melanomas (yellow). CDKN2A encodes two inhibitory variants of the G1–S phase. These inhibitors (tumor suppressors) are P16INK4A, which can bind to CDK4/6, preventing them from interacting with CCND1 and RB phosphorylation. When phosphorylated, RB can release an E2F factor which leads to G1–S cell cycle progression. P14ARF can bind to MDM2 which is responsible for p53 degradation. Epigenetic regulators can be altered in melanomas. IDH1/2 are enzymes that convert isocitrate to a-ketoglutarate. IDH1/2 mutations can lead to the formation of the oncometabolite D2H that can alter and silence several key regulator genes (although the exact role of IDH mutations in melanomas has not been elucidated). Hotspot mutations and amplifications in EZH2 can lead to aberrant methylation of H3K27, leading to dysregulation of transcriptional factors. Alterations in c-KIT and NTRK fusions (although rare in melanomas) can contribute to melanomagenesis through downstream signaling of several pathways, including MAPK and PI3K, to drive cellular proliferation. Abbreviation: RTK: receptor tyrosine-kinase; NTRK: neurotrophic tyrosine receptor kinase; PIP3: phosphatidylinositol 3; PI3K: phosphoinositide 3-kinase; PTEN: phosphatase and tensin homolog; NF1: neurofibromatosis type 1; RAS: rat sarcoma; RB: retinoblastoma; E2F: E2 factor; CDK4/6: cyclin-dependent kinase 4/6; CCND1: cyclin D1; MDM2: mouse double minute 2 homolog; MEK: mitogen-activated protein kinase; CDK2NA: cyclin-dependent kinase inhibitor 2A; ERK: extracellular signal-regulated kinase; AKT: ak strain transforming; NADP+/NADPH: nicotinamide adenine dinucleotide phosphate; IDH1: isocitrate dehydrogenase 1; NF-kB: nuclear factor kappa-light-chain-enhancer of activated B cells; mTOR: mammalian target of rapamycin; BAD: BCL2 associated agonist of cell death; BAX: BCL2-associated X protein; BCL2: B-cell lymphoma 2; IDH2: isocitrate dehydrogenase 2; EZH2: enhancer of zeste homolog 2.
Figure 3
Figure 3
Frequency of common somatic mutations in melanomas are estimated based on Vanni et al.’s analysis of the frequency of somatic mutations from different studies [33]. Fusion gene frequencies were obtained from non-TCGA database, and the frequency varies among different studies. Arrows indicate the presence of FDA-approved inhibitors in cancers harboring mutations for the specific gene in non-melanoma cancers. Orange asterisks indicate the presence of ongoing trials in melanoma patients with mutation-specific alterations or melanoma patients receiving targeted therapy for the specific mutant gene. TCGA: the cancer genome atlas; FDA: food and drug administration.
Figure 4
Figure 4
Clinical trials and retrospective study results of c-KIT inhibitors in melanomas [60,61,62,63,64,65,66,67,68,69,70]. (A) Median progression-free survival and overall survival in melanoma patient cohorts treated with different c-KIT inhibitors. These trials and retrospective studies must not be compared as patient inclusion criteria, trial designs, and KIT mutation subtypes are different. (B) Overall response rates in melanoma cohorts treated with c-KIT inhibitors. * Kalinsky et al. study analyzed PFS and OS in melanoma patients with KIT mutations involving exons 11 and 13 only [69]. PFS: progression-free survival; OS: overall survival.
Figure 5
Figure 5
Frequency of commonly mutated genes of the HR-DDR pathway in melanomas from different cohorts including: FoundationOne medicine (n = 1986), cBioPortal (1088), CPMCRI (84), and NGS600/Hotspot (n = 670) cohorts. Bar charts represent the percentage of specific gene mutations in each cohort. Pie charts represent the percentage of melanoma samples with at least one mutation in the HR-DDR pathway. HR-DDR: Homologous recombination-DNA damage response. Pie charts: blue color represents the percentage of melanoma specimens harboring at least 1 mutant gene from homologous recombination pathway. The orange color represents percentage of melanoma specimens without homologous recombination gene mutations. CPMCRI: California Pacific Medical Center Research Institute. NGS: Next-generation Sequencing.
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