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19 February 2020

Current Advances in the Treatment of BRAF-Mutant Melanoma

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1
James. L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH 45243, USA
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College of Medicine, Northeast Ohio Medical University, Rootstown, OH 44274, USA
3
College of Medicine, University of Cincinnati, Cincinnati, OH 45243, USA
*
Author to whom correspondence should be addressed.
Cancers2020, 12(2), 482;https://doi.org/10.3390/cancers12020482
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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.

1. Introduction

Melanoma is the uncontrollable division of melanocytes located within the deep layer of the epidermis [1]. Although invasive melanoma is the third most common type of skin cancer, it is the most serious compared to its other two counterparts- basal cell carcinoma and squamous cell carcinoma. The American Cancer Society estimates that in 2019 there will be 96,480 new cases of melanoma diagnosed accompanied by 7,230 expected deaths. The five-year survival rate for metastatic melanoma has been 15–20% [2], although these statistics are rapidly improving with the success of immune checkpoint inhibitors. Treatment with immune checkpoint inhibitors demonstrated substantial clinical efficacy along with long-term survival outcomes in patients with advanced melanoma [3,4,5]. There are several clinical trials such as KEYNOTE-002, CheckMate067 and CheckMate064, which validate these findings, as detailed in Table 1.
Table 1. Summary of clinical trials, outcomes and adverse events associated with anti-PD-1/PD-L1, anti-CTLA-4 and their combination in metastatic melanoma patients.
An important risk factor for melanoma is exposure to direct and chronic ultraviolet (UV) radiation which, increases the risk for DNA damage and leads to genetic changes. Familial history is also one of the risk factors for developing melanoma, with cyclin-dependent kinase inhibitor 2A (CDKN2A) and cyclin-dependent kinase 4 (CDK4) being the most common heritable mutations [1]. Germ-line polymorphisms of the melanocortin-1 receptor (MC1R) also confers susceptibility due to its ability to control the level of skin pigmentation in response to UV radiation [2,6].
The molecular changes occurring in the progression of melanoma serve as points for therapeutic interference. Typically, the preliminary change of a melanocyte into a benign nevus remains controlled and is non-cancerous. However, some molecular changes can lead to overactivation of growth regulatory pathways, such as the mitogen-activated protein kinase (MAPK) signaling pathway [2]. The MAPK pathway is crucial in relaying extracellular signals in order to keep a balance of growth/proliferation and apoptosis within the cell. A mutation within MAPK pathway leads to uncontrollable growth and ultimately develops into cancer [7]. The most common driver mutation that leads to this characteristic overactivation in the MAPK pathway is the B-RAF mutation [2]. Raf is a family of oncogenic serine-threonine protein kinases within the MAPK pathway with three isoforms: A-RAF, B-RAF, and C-RAF [7,8]. B-RAF-mutant melanoma accounts for nearly 50% of metastatic melanoma cases. Substitution of valine (V) for glutamic acid (E) at amino acid position 600 (V600E) represents 84.6% of the B-RAF mutations. A second common substitution of valine (V) for lysine (K) at amino acid position 600 (V600K), representating 7.7% of the B-RAF mutations [9]. B-RAF mutant melanoma is typically found in younger patients and is characterized by a superficial spreading tumor or nodular tumor that can be found in areas without chronic sun exposure. It has a higher chance of metastasizing into brain along with a shorter survival time as compared to the non-BRAF mutant melanoma. A B-RAF mutation alone may not contribute to the development of melanoma; but accompanying driver mutations in tumor suppressor genes are commonly indispensable leading to the development of malignant melanoma [9].
Several studies have addressed the need for molecular testing with respect to B-RAF mutations in order to tailor the best course of treatment available for each patient. [9,10]. Treatment options include surgery, immunotherapy, targeted therapy, chemotherapy, inclusion in a clinical trial and radiation [11]. Stage I and II melanoma can typically be surgically excised in concert with a sentinel lymph node biopsy if there is concern for metastasis. Stage III and IV melanoma require more systemic interventions due to the aggressiveness of the tumor and increased tumor burden [8]. The current standard of care for a patient diagnosed with B-RAF mutant metastatic melanoma is to first consider eligibility for a metastasectomy. Regardless of qualifications for the metastasectomy, the next step is to design a treatment regimen with either checkpoint inhibition immunotherapy or a molecularly targeted therapy [9,10].
Current targeted therapies include a combination of B-RAF and MEK inhibitors. Vemurafenib was the first FDA-approved B-RAF inhibitor in 2011, followed by approval of dabrafenib in 2013 [8]. The most recent FDA-approved B-RAF inhibitor is encorafenib, approved in 2018 [12]. In parallel with the discovery and use of B-RAF inhibitors opened up the avenue for development of MEK inhibitors, targeting a molecule downstream of the B-RAF protein. The first MEK-inhibitor, trametinib, was approved by FDA in 2013, followed by approval of cobimetinib in 2015 [8]. Another recently FDA-approved MEK inhibitor was binimetinib [12]. Current combinations of BRAF and MEK inhibitors that have demonstrated improved patient outcomes include dabrafenib with trametinib, vemurafenib with cobimetinib or encorafenib with binimetinib [13]. Treatment with BRAF and MEK inhibitors has met with some 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.
Current immunotherapies include the anti-cytotoxic T-lymphocyte antigen 4 antibody (anti-CTLA-4) and two anti-programmed death protein 1 antibodies (anti-PD1) [8]. Current preclinical and clinical trials are underway to determine the efficacy and benefits of combining immunotherapy treatment regimen alone or in combination with BRAF and MEK inhibitors for treatment of patients with BRAF mutant melanoma [13,14,15,16]. New avenues exploring the possible combination therapies of BRAF/MEK inhibitors with immunotherapy drugs are being tested. Combination therapies are not only limited to MAPK pathway targeted therapies plus immunotherapy but have expanded to include other molecules such as AXL and ROS that have a role in the development of drug resistance. These have emerged as alternative treatment options for treating metastatic melanoma patients. Preclinical and clinical trials evaluating the efficacy of various PI3K and CDK4/6 inhibitors in combination with BRAF and MEK inhibitors are also initiated [17,18,19,20,21,22].
This review focuses on the current landscape of resistance 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 melanoma.

2. Mechanisms of Resistance

The development and use of the BRAF targeted inhibitors, Vemurafenib and dabrafenib, has improved the treatment arena for patients with metastatic melanoma. However, over half of patients treated with these single agent inhibitors begin to show signs of tumor recurrence within 6 to 7 months of treatment [23,24]. Several mechanisms of drug resistance have been proposed. There are two general types of resistance—primary resistance/intrinsic resistance and secondary or acquired resistance. Intrinsic resistance refers to those patients who do not respond to any type of BRAF inhibitor therapy and accounts for approximately 15% of patients [25]. Acquired resistance, refers to those patients who show tumor regression after an initial positive response to therapy and this is commonly observed in most melanoma patients [26].

2.1. Intrinsic Resistance

PTEN is a negative regulator of phosphoinositde 3-kinase (PI3K) and loss of PTEN can lead to an upregulation of the PI3K/Akt pathway whose activation can explain tumor resistance [27,28]. Loss of PTEN alone does not confer a resistance state; it is typically accompanied with Akt phosphorylation and activation [26,29]. Cyclin D1 amplification (CCND1) is observed in about 15–20% of all BRAF-mutant melanoma [30,31]. CCND1 alone can accelerate the resistance in BRAF-mutant melanoma and is intensified when there is both cyclin D1 overexpression along with a cyclin dependent kinase-4 (CDK4) mutation [32].
Neurofibromin-1 (NF1) is a tumor suppressor and a negative regulator of RAS. Loss of NF1 is typically seen in 14% of melanoma cases and leads to activation of RAS and other downstream pathways including the MAPK and PI3K-Akt [26,33]. Loss of NF1 can also mediate resistance to RAF and MEK inhibitors [34].
RAC1 is part of the Rho family of small GTP binding proteins. Mutations in RAC1 are found in 4–9% of patients and is the third “hotspot” mutation in melanoma, following BRAF and NRAS [35,36,37]. RAC1 mutation status is being considered a biomarker for resistance to RAF inhibitor therapy [35]. It has been shown that pre-existing mutations in MEK1 can confer resistance to RAF inhibitor therapy [38].

2.2. Acquired Resistance

Starting from the cell surface, several receptor tyrosine kinases (RTK) converge onto parallel pathways such as the MAPK and the PI3K-Akt pathway [39]. Upregulation of RTKs has been shown to directly activate the MAPK pathway via RAS activation [30]. Additionally, upregulation of specific RTKs such as the insulin like growth factor 1 receptor (IGFR1), platelet derived growth factor receptor β (PDGFRβ) can activate the PI3K-Akt pathway in a non-ERK dependent manner [40,41]. Epigenetic changes affecting epidermal growth factor receptor (EGFR) have been shown to also induce the PI3K-Akt pathway in melanoma resistant cells [42]. Dual activation of these pathways strongly contributes to drug resistance, as these pathways promote cell survival and proliferation.
NRAS activating mutations are present in approximately 15–20% of melanomas [43]. Q61 mutations in NRAS keeps it constitutively active in the ‘RAS-GTP’ state [44]. The activated mutant NRAS can activate the MAPK pathway via induction of dimerization of CRAF and BRAF [45].
Treatment with BRAF inhibitors will only inhibit the mutant monomer in BRAF mutant melanoma cells [46]. This plays an important role in the ability for these cells to maintain RAF dimerization which in turn keeps MAPK signaling active. A phenomenon known as the ‘BRAF-inhibitor Paradox’ describes the event in which the BRAF inhibitor blocks MAPK signaling in mutant cells but activates the MAPK pathway in non-mutant cells by allowing the drug-free RAF protein to be transactivated and dimerize [47]. RAF dimerization can be fulfilled through a variety of mechanisms including alternative BRAF splicing, amplification of BRAF, and expression of different RAF isoforms such as CRAF overexpression [48,49,50,51]. Resistance to RAF inhibition include activation of HGF and its receptor MET which lead to the reactivation of the MAPK and PI3K-AKT pathways [52]. Screening for the presence of RAF inhibitor resistance genes, found in a high percentage of patients can help improve treatment outcomes especially when used in conjunction with appropriate therapeutic combinations [53].
Secondary mutations in both MEK1 and MEK2 have also been linked to acquired resistance in melanoma cell lines [54]. The resistance to MEK inhibitors is attributed to mutations in MEK1/2 which lead to constitutive activation of MEK1/2 or a mutation in the drug binding site [55]. MAPK reactivation occurs via secondary mutations in MEK1 (Q56P or E203K) which help reactive the MAPK pathway downstream [56]. Additionally, BRAF amplification along with KRAS mutations can be contributing factors to MEK1/2 inhibitor resistance [57].
The RTK AXL has also been identified as a player in both intrinsic and acquired resistance. Patients relapsed of BRAF and MEK inhibitors overexpress AXL as an adaptive response [58]. Non-genomic mechanism of acquired resistance include high expression of transcriptomic alterations and intra-tumoral immunity which involves cytolytic T-cell inflammation [59].
Combination therapy using BRAF and MEK inhibitors has also shown signs of resistance. Proposed mechanisms of resistance include BRAF gene amplification, BRAF splice-variants and mutations in MEK2 [60]. Resistance to BRAF and MEK inhibitors exists by combining or augmenting the mechanisms related to single agent BRAF inhibitor resistance. The overexpressed BRAFV600E and MEK mutants interact via the regulatory interface of BRAFV600E, R662 [61]. Acquired resistance to combination targeted therapy has other factors contributing to it, including whether the patient had received inhibitor monotherapy prior to the combination therapy or is ‘monotherapy naïve’ [62].
Many recent advancements in the treatment of metastatic melanoma have been in the field of immunotherapy. There are proposed mechanisms of resistance to BRAF and MEK inhibitor therapy involving immune system molecules. Cancer cells, in general, aim to avoid immune recognition by downregulating surface receptors that participate in co-activation of T cells as well as upregulating negative feedback pathways, such as the immune checkpoint inhibitor receptors programmed cell death protein (PD-1) and T-lymphocyte associated protein-4 (CTLA-4). PD-1 and CTLA-4 are localized on the T-cells [63]. It is documented that after 2 weeks of treatment with BRAF and MEK inhibitors, melanoma cells have been able to downregulate melanoma differentiation antigens (MDA) surface expression, decrease T cell activity, and surface display of increase immune checkpoint inhibitory receptors [64,65]. This manipulation of key immune system regulators gives melanoma cells yet another way to bypass drug resistance. The rationale to combine an immune checkpoint inhibitor therapy with targeted therapy is that the treatment with a BRAF and MEK inhibitor renders the tumor microenvironment more immunoresponsive [66].
The sequence of treatment for a patient with targeted therapy and immune therapy is not well established. Starting a patient on a BRAF inhibitor or anti-PD1 inhibitor is effective regardless of the treatment order, but more randomized controlled trials are required to address and establish the superiority and sequencing of one therapy over the other [67,68]. Studies have also shown that the efficacy of immunotherapy is improved in previously untreated patients compared to patients who have single agent immunotherapy failure or failure to targeted therapy [69]. Despite showing exceptional clinical efficacy, treatment with immune checkpoint inhibitors has met some difficulties with respect to development of innate and acquired resistance [70,71]. Various clinical trials evaluating immune therapies such as Toll-like receptor 9 (TRL9) agonists, neoantigen vaccines and oncoloytic viruses alone or in combination with immune checkpoint inhibitors are underway. Combination of these therapies may help combat resistance to immune checkpoint inhibitors [72,73,74,75,76,77].

3. Therapies

Figure 1 summarizes the therapies in pre-clinical and clinical phases, described in this review to treat patients with metastatic melanoma.
Figure 1. Novel therapies in pre-clinical and clinical phases (Anti PD-1/anti-PD-L1, anti CTLA-4, AXL inhibitors. BRAF inhibitors. ERK inhibitors and ROS activated prodrugs) to treat patients with metastatic melanoma (created with BioRender; www.biorender.com).

4. Anti-PD-1/PD-L1

The immunogenic nature of melanoma was utilized to develop several immunotherapeutic treatment strategies especially with regards to the programmed cell death (PD-1) receptor and its ligand, PD-L1. Antibodies targeting the PD-1 axis has shown significant promise in the clinic for treatment of metastatic melanoma either as a monotherapy or in combination with Ipilimumab. There are several ongoing clinical trials using anti-PD1 and anti-PD-L1 antibodies. Programmed cell death protein 1 (PD-1) is an inhibitory receptor expressed on the surface of the cancer cells that inhibits the immune system via suppressing the T-cell activity. Anti-PD-1 monoclonal antibodies block the PD-1 receptor which maintains T-cells in activated state to suppress the tumor growth [78]. There are several anti-PD-1/PD-L1 monoclonal antibodies including pembrolizumab (Keytruda®), nivolumab (Opdivo®), avelumab (Bavencio®), durvalumab (Imfinzi®), cemiplimab (Libtayo®), atezolizumab (Tecentriq®), cosibelimab and INBRX-105 in several stages of clinical trial in melanoma. Pembrolizumab, nivolumab and nivolumab in combination with iIpilimumab (anti-CTLA-4 inhibitor) have been approved by FDA for treatment of melanoma.

4.1. Pembrolizumab/Lambrolizumab/MK-3475/SCH 900475/Keytruda

This is a humanized monoclonal antibody targeting the PD1 receptor in the lymphocytes. It was developed by Merck and approved for treatment of metastatic melanoma in 2017 [79].

4.2. Nivolumab/ONO-4538/BMS-936558/MDX1106/Opdivo

This is a human IgG4 anti-PD-1 monoclonal antibody. Nivolumab works as a checkpoint inhibitor that inhibits T-cell activation. [80]. It was developed by Medarex and Ono Pharmaceutical, and is marketed by Bristol-Myers Squibb (BMS) and Ono. Nivolumab was approved by the FDA for melanoma in 2014 [81,82].

4.3. Avelumab/MSB0010718C/Bavencio

This is a humanized monoclonal antibody developed by Merck and Pfizer that targets the PD-L1. It has been approved by FDA for treatment Merkel-cell carcinoma, an aggressive type of skin cancer [83]. It blocks the PD-1/PD-L1 receptor/ligand complex formation leading to suppression of CD8+ T cells action [84]. There is a current clinical trial (NCT01772004) investigating the safety, tolerability, pharmacokinetics and clinical activity of avelumab in melanoma [85].

4.4. Durvalumab/MEDI4736/Imfinzi

This is monoclonal antibody that blocks the interaction of PD-L1 with the PD-1 and CD80 (B7.1) molecules developed by Medimmune/AstraZeneca [86,87]. A phase I clinical trial (NCT02586987) is ongoing evaluating the safety and efficacy of selumetinib (AZD6244 Hyd-sulfate) in combination with durvalumab (MEDI4736) along with tremelimumab in patients with advanced solid tumours, including melanoma [88].

4.5. Atezolizumab/MPDL3280A/Tecentriq

This is a fully humanized engineered monoclonal antibody of IgG1 isotype against PD-L1 developed by Genentech [89,90]. There is an active ongoing phase II trial (NCT02303951) which includes the combination of vemurafenib, cobimetinib and atezolizumab in stage III/IV advanced melanoma patients [91]. Another phase III study (NCT02908672) compares the efficacy of atezolizumab in combination with cobimetinib and vemurafenib versus placebo control plus cobimetinib and vemurafenib in unresectable and advanced melanoma patients with BRAFV600 mutation [92].

4.6. Spartalizumab/PDR001

Spartalizumab (PDR001) is a humanized monoclonal antibody against the negative immuno-regulatory human cell surface receptor programmed death-1 (PD-1, PCD-1) was developed by Novartis. This suppresses T-cell activation as it binds to PD-1 on activated T-cells and inhibits the interaction with its ligands, (PD-L1, PD-1L1) and (PD-L2, PD-1L2) [93]. A phase I/Ib (NCT03891953) study evaluating the efficacy of spartalizumab in combination with DKY709 (immunomodulatory agent) in patients with advances solid tumors including melanoma is ongoing [94]. A phase II PLATforM (NCT03484923) study evaluating the efficacy and safety of spartalizumab in combinations with LAG525 (monoclonal antibody targeting LAG-3), capmatinib (MET inhibitor), canakinumab (monoclonal antibody targeting IL-1β) and ribociclib (CDK4/6 inhibitor) is ongoing in previously treated unresectable or metastatic melanoma [95]. A phase III COMBI-i study (NCT02967692) comparing the combination of spartalizumab, dabrafenib and trametinib versus dabrafenib and trametinib in previously untreated patients with unresectable or metastatic BRAFV600 mutant melanoma is initiated [96].

5. Anti-CTLA-4

In addition to PD-1, another immune checkpoint inhibitor, cytotoxic T-lymphocyte antigen 4 (CTLA-4), is important in melanoma. It is found on the surface of regulatory T cells (Treg) and activated T cells [97]. CTLA-4 competes with CD28, another receptor expressed on the surface of T cells, to interact with its two ligands CD80 and CD86, collectively known as the B7 ligands. When CTLA-4 binds with the B7 ligands, commonly found on antigen presenting cells (APC), it results in an immunosuppressive response, which is the inhibition of T cell activation via transendocytosis of CD80 and CD86 from their surfaces [98,99]. Typically, T cell activation requires co-stimulation from the CD28-B7 ligand interaction and the TCR-MHC interaction [100]. However, CTLA-4 has a stronger affinity for the B7 ligands, making it a good immune checkpoint inhibitor that keeps the immune response from turning into an autoimmune one [97]. CTLA-4 is expressed on tumor cells, infiltrating Tregs, and exhausted, activated T cells [101]. Tumor cells, therefore, take advantage of this natural immunosuppressive system in order to prevent an immune response against them. This provides a therapeutic approach which involves anti-CTLA-4 therapy. There are currently three main anti-CTLA-4 antibodies under preclinical and clinical trials for the treatment of melanoma: Tremelimumab, Ipilimumab (Yervoy), and BCD-145.

5.1. Tremelimumab/Ticilimumab/CP 675.206

This human monoclonal antibody against CTLA-4 was developed by AstraZeneca [102]. A phase I active, clinical trial (NCT02141542) is -evaluating tremelimumab in combination with MEDI3617 (human anti-angiopoietin 2 monoclonal antibody) for unresectable Stage III/IV melanoma patients [103]. Another phase I active, clinical trial (NCT01103635) is examining tremelimumab in combination with CP-870,893 CD40 agonist monoclonal antibody) for metastatic melanoma [104].

5.2. Ipilimumab/MDX010/BMS-734016

This human monoclonal antibody against CTLA-4 was developed by YERVOY Medarex/BMS. It was approved by the FDA in 2011 for the treatment of unresectable or metastatic melanoma [105]. There are current, active clinical trials devoted to assess the efficacy of ipilimumab in combination with other immunotherapies or targeted therapies for metastatic melanoma. A phase I clinical trial (NCT02115243) that assessed ipilimumab as a neoadjuvant followed by melphalan (chemotherapeutic) via isolated limb perfusion in patients with unresectable in-transit extremity melanoma is completed [106]. A phase Ib clinical trial (NCT02117362) evaluating ipilimumab in combination with GR-MD-02 (galnectin inhibitor) in metastatic melanoma patients has been completed [107]. A phase II clinical trial (NCT03153085) examining ipilimumab in combination with TBI-1401(HF10) in Japanese patients with Stage IIIb, IIIc, IV unresectable or metastatic malignant melanoma has been completed [108]. A phase II clinical trial (NCT01970527) looking at SBRT followed by Ipilimumab in patients with stage IV and recurrent melanoma has been completed [109].

5.3. BCD-145

This human monoclonal antibody against CTLA-4 is developed by BIOCAD [110]. A completed phase I clinical trial (NCT03472027) studied the efficacy of BCD-145 in unresectable/metastatic melanoma [111]. The combination of anti-PD-1/PD-L1 and anti-CTLA-4 are also being tested in the clinic for stage III/IV melanoma patients. A phase I clinical trial (NCT02935790) evaluating ipilimumab and nivolumab in combination with ACY-241 (selective HDAC inhibitor) is completed [112]. Current clinical trials, outcomes and adverse events investigating the efficacy of anti-CTLA-4, anti-PD-1/PD-L1 therapies and their combinations used to treat metastatic melanoma patients are listed in Table 1 [113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160].

6. AXL Inhibitors

The TAM family of receptor tyrosine kinases (RTKs) is comprised of Tyro-3, Axl and Mer (TAM). These TAMS regulate cell proliferation, survival, adhesion, migration, invasion and metastasis of neoplasms [161]. The AXL gene is located on chromosome 19q13.2; encoded by 20 exons. The protein structure consists of an extracellular domain consisting of a combination of two IgG like domains and two fibronectin type III repeats; a conserved intracellular kinase domain and a transmembrane domain [162,163]. Even though all three TAMS have transforming potential, the aberrant overexpression of Axl is associated with cancer progression, drug resistance and supports tumor immune escape in several cancers including melanoma [164,165,166,167,168,169,170,171,172]. In primary and acquired resistance in melanoma, Axl levels inversely correlate with levels of melanocyte lineage factor- Microphthalmia-associated transcription factor (MITF). The high Axl, low MITF drug resistance phenotype is found frequently among BRAF mutant melanoma cell lines. This is associated with a phenotype switch of cells form proliferative to an invasive phenotype and promotes metastasis [165,173,174]. The Axl inhibitors can be classified into 2 types. Type I encompasses inhibitors that compete with ATP and bind to the active conformation of the receptor, DGF-in (constitutes of the aspartate-phenylalanine-glycine (DFG) motif oriented towards the active site). Type II inhibitors interact with the DFG residues of the activation loop which open up an allosteric region, adopt an extended conformation and prefer binding to the inactive DFG-out conformation. [175]

6.1. BGB-324/Bemcentinib (Type I)

This highly selective orally bioavailable inhibitor was developed by BerGenBio [176]. Upregulation of Axl leads to drug resistance of BRAF directed therapies in the context of melanoma and also reduces response to PD-1 blockade. A Phase Ib/II trial is ongoing (NCT02872259) evaluating BGB324 in combination with dabrafenib/tramatenib or pembrolizumab in advanced non-resectable Stage IIIc/IV melanoma. The interim results for this study indicate that the combination was well tolerated at the recommended phase 2 dose of 200 mg daily of Bemcentinib. The common adverse events were diarrhea, fatigue, rash and pyrexia [177].

6.2. TP-0903 (Type I)

This oral Axl kinase inhibitor was developed by Tolero Pharmaceuticals, Inc. A first-in-human phase Ia/Ib trial (NCT02729298) evaluating TP-0903 in patients with advanced solid tumors encompassing BRAF mutated melanoma patients who haven’t responded to BRAF/MEK inhibitor combination or immunotherapy is currently recruiting patients [178,179].

6.3. Cabozantinib/XL184/BMS-907351 (Type II)

This inhibitor, developed by Exelixis [180], is an orally bioavailable small molecule inhibitor against various tyrosine kinases which include Axl, MET and VEGF. A phase II trial (NCT00940225) evaluating cabozantinib in patients with metastatic melanoma was discontinued as the study was underpowered to detect statistical significance [181]. A phase I/II trial (NCT03957551) evaluating the combination of cabozantinib and pembrolizumab as a front-line therapy has been initiated for patients with advanced metastatic melanoma [182].

6.4. LDC1267 (Type II)

This inhibitor preferentially inhibits Axl, Mer and Tyro3. In an in vivo model, it was observed that treatment with LDC1267 unleashes natural killer (NK) cells to target and kill tumor cells. Treatment with LDC1267 reduced the metastatic spreading of melanoma in an in vivo B16F10 melanoma model [183]. Further pre-clinical and clinical trials need to be initiated to test the efficacy of this drug in melanoma.

6.5. AXL-1047-MMAE

This is an antibody-drug conjugate (ADC) in which the Axl targeting human antibody is conjugated to monomethyl auristatin E (MMAE), a microtubule disrupting agent by a valine citrulline linker which is protease-cleavable. This ADC induces cytotoxicity in vitro and in vivo in melanoma models. Treatment with the ADC prevents the emergence of BRAF-inhibitor resistant clones and potentiates the efficacy of BRAF and MEK inhibitors and co-operatively targets the growth of resistant cells. This ADC along with BRAF and MEK inhibitors has shown efficacy in treatment naïve and MAPK pathway inhibitor resistant melanoma. A phase I/II trial (NCT02988817) evaluating enapotamab vendotin (HuMax-AXL-ADC) has been initiated in patients with solid tumors, including melanoma [184,185]

7. BRAF Inhibitors

BRAF inhibitors are small molecule inhibitors that selectively target mutant BRAF isoforms, preferentially V600E but also other isoforms such as V600K or V600D [186]. BRAF inhibitors are typically used in combination with inhibitors of MEK, the downstream target of BRAF, in order to delay the development of resistance to BRAF inhibitor monotherapy as in the current standard of care for late-stage BRAFV600E melanoma, dabrafenib and trametinib. Vemurafenib/PLX4032/RG7204, a serine/threonine kinase inhibitor, was the first selective BRAF inhibitor that was approved by the FDA. It binds to the ATP-binding domain of BRAF mutants such as V600E, V600R and V600D [187]. 960 mg twice daily was established as the recommended phase 2 dose in the phase 1 (NCT00405587) dose escalation clinical trial [186]. The FDA approval was granted based on the Phase 3 trial (BRIM-3) results (NCT01006980) which exhibited improved overall survival and progression-free survival rate in patients with BRAFV600E mutant melanoma [188]. Dabrafenib, a type I-kinase inhibitor was the second BRAF inhibitor that was approved by the FDA. This reversible ATP-competitive inhibitor, inhibits BRAFV600E, V600D and V600K proteins [189]. The Phase 2 trial (BREAK-2; NCT01153763) trial established a dose of 150 mg twice daily which can either be used as a single agent or in combination with trametinib [190,191]. It was granted FDA approval on the basis of the outcomes of Phase 3 trial (NCT01227889) in which it exhibited improved progression-free survival vs. decarbazine [24].

Encorafenib/LGX818

This molecule is an oral BRAF inhibitor selective for BRAFV600E that was approved by the FDA in June 2018 for use in combination with the MEK inhibitor binimetinib (MEK162) in treating metastatic melanoma patients with the BRAFV600E mutation [192]. A phase II trial (NCT02631447) to determine the optimal sequencing of BRAFi + MEKi (encorafenib + binimetinib) therapy and immunomodulatory antibody (ipilimumab + nivolumab) therapy in stage III-IV metastatic BRAF V600 melanoma is ongoing [193]. A phase II trial (NCT02159066) evaluating the use of third agent in encorafenib + binimetinib therapy in stage III-IV metastatic BRAF V600 melanoma [194].

8. MEK Inhibitors

MEK inhibitors are small molecule inhibitors targeting MEK1/2 proteins in the MAPK pathway. The addition of a MEK inhibitor in combination with a BRAF inhibitor delayed the development of resistance and decreased the toxicities associated with BRAF inhibitor monotherapy [195]. Trametinib/GSK1120212, a reversible, non-ATP-competitive inhibitor of MEK1/2 was the first MEK inhibitor approved by the FDA. The phase 1 study (NCT00687622) identified 2 mg daily dose of trametinib, which could be safety, administered to the patients [196]. The phase 3 COMBI-D trial (NCT01584648) provided evidence of combining dabrafenib and trametinib in patients with metastatic BRAFV600E/K mutant melanoma as compared to monotherapy with dabrefenib [197]. Cobimetinib/GDC-0973 is used in combination with vemurafenib and is approved for patients with BRAFV600E/K mutant metastatic melanoma. The FDA approval was granted based on the efficacy results of combination of vemurafenib and cobimetinib in Phase-3 co-BRM trial (NCT01689519) [198]. Binimetinib/MEK162 is used in combination with encorafenib and is used in patients harbouring BRAFV600E/K mutation.

8.1. KZ-001

This selective MEK1/2 inhibitor is a benzoxazole compound with high potency and exhibits anti-tumor activity in BRAF- and NRAS-mutant tumor cell lines. It presented a synergistic effect in in vitro and in vivo xenograft models when used in combination with docetaxel (microtubule-stabilizing chemotherapeutic agent) and vemurafenib [199].

8.2. E6201

This MEK1 inhibitor was developed by Eisai Inc. This ATP-competitive MEK inhibitor is a synthetic analog of a natural product f152A1 occuring from the fungus Curvularia verruculosa [200]. NCT00794781 was a Phase I trial, evaluating the efficacy and safety of E6201 in patients with BRAF mutant advanced melanoma was terminated early due to futility based on response data [201].

8.3. TAK-733

This selective, oral, potent, non-ATP competitive allosteric site MEK inhibitor was developed by Millenium Pharmaceuticals, Inc. It demonstrated anti-tumor effects in vitro in melanoma cell lines and in vivo in patients-derived xenograft models [202]. NCT00948467 was a Phase 1 dose escalation trial evaluating TAK-733 in advanced solid tumors including patients with advanced metastatic melanoma had manageable toxicity profile but had limited antitumor activity and based on this result the further investigations are not planned [203].

8.4. PD-0325901/Mirdametinib

This selective, potent, oral, noncompetitive MEK inhibitor was developed by Pfizer. It inhibited ERK phosphorylation in in vitro model. It inhibited growth of melanoma cell lines in vitro and in xenograft models. This molecule also inhibited angiogenesis by inhibiting VEGF production and induced apoptosis in in vitro models [204]. NCT00147550, a phase I/II clinical trial evaluating the efficacy of PD-0325901 in advanced melanoma has been terminated due to ocular, neurological and musculoskeletal toxicities at higher doses (> 15 mg twice a day) [205].

9. ERK Inhibitors

ERK plays a unique role in the MAPK/ERK pathway; it has more than 100 substrates, some of which are involved in MAPK/ERK activating/de-activating feedback loops, yet it has only one upstream effector, MEK1/2 [206]. Due to this role, ERK inhibitors may show promise as a method of overcoming the development of resistance and re-activation of BRAF and MEK in BRAFV600E melanoma. While presently far behind BRAF and MEK inhibitors in development, there has been a recent increase in the development and evaluation of ERK inhibitors for treating BRAFV600E melanoma.

9.1. Ulixertinib/BVD-523

Ulixertinib is a novel, selective ERK1/2 inhibitor developed by BioMed Valley Discoveries, that inhibits ERK1/2 in a reversible and competitive manner. Importantly, ulixertinib presented equivalent efficacy in BRAF mutant cells and BRAF + MEK double mutant cells, while the efficacy of BRAF and MEK inhibitors decreased in the double mutant line [207]. Currently, it has been designated for fast track status by the FDA in the treatment of metastatic BRAFV600E-mutant melanoma [208].

9.2. LY3214996

A selective ERK1/2 inhibitor developed by Eli Lilly currently in phase I clinical trials [209,210]. Further details of this pre-clinical characterization have not been made publicly available, and Phase I trials are on-going.

9.3. MK8353

An orally dosed, selective inhibitor of activated ERK1/2, and non-activated ERK2 developed by Merck & Co. currently recruiting for phase I trials [211,212]. A phase I clinical trial was initiated following these results in healthy volunteers (NCT01358331); however, the study was terminated after phase Ia MTD determination (400 mg orally once daily) for strategic reasons [213].

9.4. LTT462

An oral ERK inhibitor developed by Novartis. LTT-462 has completed a phase I clinical trial for use in advanced cancers, including melanoma. A phase I clinical trial (NCT02711345) evaluating the use of LTT462 in advanced melanoma and other advanced cancer has concluded; however, the results are not yet publicly available [214].

9.5. KO-947

A highly potent and selective ERK1/2 inhibitor developed by Kura Oncology [215].

9.6. GDC0994

An orally-dosed, selective ERK1/2 inhibitor developed by Genentech [216]. A phase Ia trial (NCT01875705) was conducted on MAPK-dysregulated cancers not including melanoma. The phase Ia trial found a safety profile consistent with MAPK inhibition with tolerable adverse events [217]. A following phase Ib trial (NCT02457793) investigating the use of GDC0994 in combination with cobimetinib (MEKi) in advanced cancers including advanced melanoma has completed; however, the comprehensive results have not yet been released [218].

9.7. SCH772984

This is a selective, ATP-competitive ERK inhibitor developed by Merck. It exhibits antitumor activity against BRAFV600E mutant and NRAS mutant melanoma. It blocks proliferation of melanoma cell lines in BRAF and MEK inhibitor resistant cell lines in vitro [219]. The synergistic combination of SCH772984 with Vemurafenib delayed the onset of acquired resistance in in vitro models [220]. Intermitent dosing with RAF inhibitor, MEK inhibitor and ERK inhibitor (SCH772984) inhibited tumor growth in low-level BRAF amplification patient derived xenograft model of melanoma [221].
Table 2 summarizes the clinical trials, outcomes and adverse effects of novel BRAF and ERK inhibitors that are under investigation in the clinic to treat metastatic melanoma patients [211,222,223,224].
Table 2. Summary of clinical trials, outcomes and adverse events associated with novel BRAF inhibitors and ERK inhibitors in patients with metastatic melanoma.

10. ROS Activated Prodrugs

Redox homeostasis is essential for cell transcription, proliferation and survival. Failure of regulating redox homeostasis can cause DNA damage and cell apoptosis [225]. Cancer cells are known to express increased reactive oxygen species (ROS) such as superoxide, H2O2 and the hydroxyl radicals [226,227,228,229]. Evidence has shown a significant increase in ROS levels after B-RAF inhibition in melanoma cells [230]. ROS-activated prodrugs can be potentially utilized in combination with B-RAF inhibitors to target metastatic melanoma cells.

10.1. Protein Ribonuclease A (RNase A)/SN-38

These ROS activated drugs usually contain two separate functional domains- a ROS-accepting moiety, “Trigger”, and an “Effector”. In the presence of H2O2, the B-C bond within the aryl Byronic acid or esters will become oxidized, releasing the phenol group and activating the pro-drug. Protein ribonuclease A (RNase A) and SN-38 are being studied in the B16F10 murine melanoma cell line which mimics primary tumor growth [231,232]. SN-38 significantly decreases the proliferation of B16F10 murine melanoma cell line [231]. The enzymatic activity of RNase A will be reduced and cytotoxicity is improved when being activated via high ROS levels against skin melanoma cancer cells (B16F10) [232]. The success of these prodrugs in reducing tumor proliferation in murine melanoma cells gives the potential to study these drugs in human melanoma cell lines and potentially into clinical trials.

10.2. A100/RAC1

A100 is a quinone derivative. Quinones have substituents on the activated alkene, which are also called Michael acceptors. Cell damage and cytotoxicity occurs through the alkylation of DNA or cellular proteins. A100 sensitizes dabrafenib-resistant melanoma cells to BRAF protein kinase inhibitors [233]. A100, in the presence of high ROS levels, can self-cyclize into a bicyclic ring and cause DNA double strand breaks in cancer cells [234]. This compound and related ROS activated pro-drugs could be useful therapeutic agents where a BRAF inhibition has failed as the first line of treatment in melanoma patients harboring BRAFV600E mutation.

11. Conclusions

Resistance to therapies continues to push the need to expand our understanding of melanoma treatment. This has led to exploring new treatments that utilizes combination therapies in order to achieve maximum anti-tumor efficacy over long durations of treatment avoiding resistance. Advances in the treatment of metastatic melanoma are on the rise with progress in targeted molecular therapy and immunotherapy. Targeted therapies are now expanding to include new BRAF and MEK inhibitors together and in combination with other therapies. Progress is being made in the field for targeting Axl and with ROS activated prodrugs. Immunotherapies are a new area of interest focusing on manipulation of checkpoint inhibition with durable clinical responses in patients. Melanoma has a strong molecular and genetic basis of pathogenicity, which allows for the development of personalized medicine. Selecting unique and individual treatments for melanoma patient makes it more likely to achieve high success rates in the clinic. Continual research and clinical trials are ongoing to further elucidate and expand knowledge on mechanisms of resistance and novel treatment strategies such as immunotherapies, new small molecule inhibitors and ROS-activated prodrugs to provide effective care to patients with metastatic melanoma.

Author Contributions

Conceptualization, H.P., J.T.G.; writing-original draft preparation, H.P., N.Y., R.M., A.W., L.Y.; writing-reviewing and editing, H.P., N.Y., R.M., S.A., J.T.G.; table preparation, H.P., R.M., A.W.; figure preparation, N.Y.; supervision, J.T.G.; revised manuscript, H.P., N.Y., J.T.G. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by DOD CDMRP PRCRP Career Development W81XWH1910441.

Conflicts of Interest

The authors declare no conflict of interest.

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