Molecular Markers and Targets in Melanoma
Abstract
:1. Introduction
1.1. Epidemiology
1.2. Risk Factors
2. Molecular Pathways of Melanoma Development
2.1. MAPK Pathway
2.2. PI3K-AKT Pathway
2.3. CDKN2A, Cell Cycle, and Apoptosis Regulation
2.4. MITF Pathway
2.5. NFκB Pathway
2.6. WNT Pathway
3. The Integration of Histology and Molecular Diagnostics of Melanoma
4. Therapeutic Targets and Current Treatment Strategies in Advanced Melanoma Patients
4.1. BRAF
4.1.1. BRAF and MEK Inhibitors
- Dabrafenib plus trametinib
- Cobimetinib plus vemurafenib
- Encorafenib plus binimetinib
4.1.2. Differences between BRAFV600E and BRAFV600K Mutations
4.1.3. Resistance Mechanisms to BRAF and MEK Inhibition
4.2. Immune Checkpoint Inhibitors: Anti-CTLA-4 and Anti-PD1
4.2.1. Anti-CTLA4
4.2.2. Anti-PD1-Based Therapies
- Combination of Anti-PD1 with Anti-CTLA-4 Monoclonal Antibodies
- Novel Combinations of BRAF/MEK Inhibitors and Immune Checkpoint Inhibitors
- Biomarkers of response and resistance mechanisms to immune checkpoint inhibitors
4.3. Other Immunotherapy Treatment Strategies: Adoptive Cell Therapy
4.3.1. Tumor-Infiltrating Lymphocytes
4.3.2. T Cell Receptor-Engineered T Cells
4.3.3. Chimeric Antigen Receptor T Cells
4.4. NRAS
4.5. C-KIT
4.6. GNAQ/GNA11
4.7. SF3B1
4.8. NTRK
4.9. Other Therapeutic Options
- NFκB pathway
- WNT pathway
5. Conclusions and Future Directions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
ACT | adoptive cell therapy; |
AE | adverse events; |
ALK | Anaplastic lymphoma kinase; |
BAD | BCL-2 antagonist of cell death |
BRAF | v-raf murine sarcoma viral oncogene homolog B1; |
BRAF | inhibitor (BRAFi) |
CAR-T | chimeric antigen receptor T cells; |
CCND1 | cyclin D1; |
CDK4 | cyclin-dependent kinase 4; |
CDKN2A | cyclin-dependent kinase inhibitor 2 receptor; |
ChT | chemotherapy; |
CSD | cumulative sun damage; |
CTLA-4 | cytotoxic T-lymphocyte–associated antigen 4; |
CTNNB1 | Catenin Beta 1; |
cuSCC | cutaneous squamous cell carcinoma; |
DVL | dishevelled; |
ERK | extracellular signal-related kinase; |
FAMMM | familial atypical multiple mole-melanoma; |
FDA | US Food and Drug Administration; |
FRZD | Frizzled receptors; |
GEP | gene expression profiles; |
GPCR | G-protein-coupled receptors; |
GSK3β | glycogen synthase kinase 3β; |
GTPase | guanosine triphosphatases; |
HRAS | v-Ha-ras Harvey rat sarcoma viral oncogene homolog; |
ICI | immune checkpoint inhibitor; |
IFNG | interferon-gamma; |
IL | interleukin; |
iNOS | inducible nitric oxide synthase; |
JNK | c-Jun N-terminal kinases; |
KRAS | v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog; |
LEF | lymphoid enhanced transcription factor; |
LRP | lipoprotein receptor; |
MAPK | mitogen-activated protein kinase; |
MAP2K1 | mitogen-activated protein kinase kinase 1; |
MAP3K1 | mitogen-activated protein kinase kinase kinase 1; |
MC1R | melanocortin 1 receptor; |
MDM2 | Mouse double minute 2 homolog; |
MEK | inhibitors (MEKi) |
MITF | microphthalmia-associated transcription factor; |
mTOR | mammalian target of rapamycin; |
NBD | NEMO-binding domain; |
NF1 | neurofibromin 1; |
NFκB | nuclear factor-kappaB; |
NTRK | Neurotrophic Tyrosine Receptor Kinase; |
NRAS | neuroblastoma ras viral oncogene homolog; |
ORR | overall response rate; |
OS | overall survival; |
PD1 | programmed cell death-1; |
PD-L1 | programmed cell death ligand-1; |
PI3K | phosphatidylinositol-3-kinase; |
PIP2 | phosphatidylinositol-4,5-diphosphate |
PIP3 | phosphatidylinositol-3,4,5-trisphosphate |
PTEN | phosphatase and tensin homolog; |
RTK | receptor tyrosine kinase; |
SF3B1 | Splicing Factor 3b Subunit 1; |
TCR-T | T-cell receptor– engineered T cells; |
TERT | Telomerase Reverse Transcriptase; |
TILS | Tumor-infiltrating lymphocytes; |
TCF | T-cell transcription factor; |
TCGA | The Cancer Genome Atlas |
TNF | tumor necrosis factor; |
TRAE | treatment-related adverse event |
TRK | tropomyosin receptor kinases; |
UV | ultraviolet; |
WHO | World Health Organization |
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UV Exposure | Categories | Melanoma Subtype | Key Molecular Genes | |
---|---|---|---|---|
Low UV/CSD | I | Superficial spreading melanoma | BRAFV600 mut CDKN2A mut NRAS mut | TERT mut PTEN mut TP53 mut |
High UV/CSD | II | Lentigo maligna melanoma | NRAS mut BRAFnon-V600E mut KIT mut TERT mut | CDKN2A mut PTEN mut TP53 mut |
III | Desmoplastic melanoma | NF1 mut NFKBIE mut | NRAS mut PIK3CA mut | |
Low or no UV/CSD | IV | Spitz melanoma | ALK rearr NTRK1 rearr NRTK3 rearr | CDKN2A mut HRAS mut |
V | Acral melanoma | KIT mut NRAS or BRAF mut ALK rearr NRTK3 rearr | CDKN2A mut CCND1 amp TERT mut | |
VI | Mucosal melanoma | KIT mut NRAS or BRAF mut CDKN2A mut SF3B1 mut | CCND1 amp CDK4 mut MDM2 amp | |
VII | Melanoma in congenital nevus | NRAS mut | BRAFV600E mut | |
VIII | Melanoma in blue nevus | GNA11 mut GNAQ mut CYSLTR2 mut | BAP1 mut EIFAX mut SF3B1 mut | |
IX | Uveal melanoma | GNA11 mut GNAQ mut CYSLTR2 mut PLCB4 mut | BAP1 mut EIFAX mut SF3B1 mut |
Trial Name | Phase | Patients | Treatment Groups | Primary Endpoint | n | ORR | PFS | OS | Reference |
---|---|---|---|---|---|---|---|---|---|
Anti-CTLA-4 | |||||||||
MDX010-020 (NCT00094653) | III | Untreaded MM | Ipi 3 + gp100 vs. Ipi 3 vs. gp100 (3:1:1) | OS | 676 | 6 vs. 11 vs. 2 | 2.8 vs. 2.9 vs. 2.8 | 10.0 vs. 10.1 vs. 6.4 | [48] |
Anti-PD1 +/− anti-CTLA-4 | |||||||||
CM-066 (NCT01721772) | III | Untreated BRAF- wild type MM | Niv 3 q2w + Placebo vs. Placebo + Dacarbazine 1000 q3w (1:1) | OS | 418 | 40 vs. 14 | 5.1 vs. 2.2 | 37.5 vs. 11.2 | [49] |
CM-067 (NCT01844505) | III | Untreated MM | Niv 1 + Ipi 3 (q3w) x4 − Niv 3; Niv 3 alone q2w, vs. Ipi 3 q3w x4 (1:1:1) | PFS and OS co-primary | 945 | 58 vs. 44 vs. 19 | 11.5 vs. 6.9 vs. 2.9 | [50] | |
CM-511 (NCT02714218) | III | Untreated MM | Niv 1 + Ipi 3 (q3w) x4 − Niv 3 vs. Niv 3 +Ipi 1 (q3w) x4 − Niv 3 (1:1) | TRAE rate (grade 3–5) | 360 | 48 vs. 34 | 8.9 vs. 9.9 | NR vs. NR | [51] |
KN-006 (NCT1866319) | III | MM ≤ 1 line (anti-PD1/PD-L1+/− anti-CTLA-4 included) | Pem 10 q2w vs. Pem 10 q3w vs. Ipi 3 q3w (1:1:1) | PFS and OS (co-primary) | 834 | 34 vs. 33 vs. 12 | 8.4 vs. 3.4 | 32.7 vs. 15.9 | [52] |
BRAFi monotherapy | |||||||||
BRIM-3 (NCT01006980) | III | Untreated MM | Vem 960 mg bd vs. DTIC (1:1) | PFS and OS (co-primary) | 675 | 48 vs. 5 | 5.3 vs. 1.6 | 13.6 vs. 9.7 | [9] |
BREAK3 (NCT01227889) | III | Untreated BRAFV600E MM | Dab 150bd vs. DTIC (3:1) | ORR | 250 | 50 vs. 6 | 6.9 vs. 2.7 | 20 vs. 15.6 | [53] |
Combined BRAFi + MEKi | |||||||||
COMBI-v (NCT01597908) | III | Untreated BRAF V600E/K MM | Dab 150 bd + Tra 2 od vs. Vem 960 bd (1:1) | OS | 704 | 64 vs. 51 | 11.4 vs. 7.3 | NR vs. 17.2 | [54] |
COMBI-d (NCT01584648) | III | Untreated BRAF V600E/K MM | Dab 150 bd + Tra 2 od vs. Dab 150 bd (1:1) | PFS | 423 | 69 vs. 53 | 11.0 vs. 8.8 | 25.1 vs. 18.7 | [55] |
CoBRIM (NCT01689519) | III | Untreated BRAFV600 MM | Cob 60 od d1-21 + Vem 960 bd vs. Vem 960 bd + Placebo (1:1) | PFS | 495 | 68 vs. 45 | 12.3 vs.7.2 | 22.3 vs. 17.4 | [56] |
COLUMBUS (NCT01909453) | III | Untreated BRAF V600E/K MM | Enc 450 od + Bin 45 mg bd vs. Enc 300 mg od vs. Vem 960 mg bd (1:1:1) | PFS | 577 | 64 vs.52 vs. 41 | 14.9 vs. 9.6 vs. 6.3 | 33.6 vs. 23.5 vs. 16.9 | [57] |
Triplet therapy (ICI + BRAFi + MEKi) | |||||||||
IMSpire150 (NCT02908672) | III | Untreated BRAFV600 MM | Ate 840 d1,15 + Vem 720 bd + Cob 60 od d1-21 vs. Placebo + Vem 960 bd + Cob 60 od d1-21 (all: q4w) | PFS | 514 | 66 vs. 65 | 15.1 vs. 10 | Not yet reported | [58] |
COMBI-I (NCT02967692) | III | Untreated BRAFV600 MM | Spa 400 mg + Dab 150 bd + Tra 2 od vs. Placebo + Dab 150 + Tra 2 (q4w) | PFS | 532 | 69 vs. 64 | 16.2 vs. 12.0 | NR vs. NR | [59] |
The Key Type of Target Mechanism | Potential Agen/Drugs | Phase | Potential Clinical Indication | ORR (%) | References |
---|---|---|---|---|---|
VEGFR1–VEGFR3, C-KIT, PDGFR | Axitinib | II Ib | Monotherapy in advanced melanoma In mucosal melanoma in combination with toripalimab (anti-PD1) | 18.8 48.3 | [60] [61] |
VEGFR1–VEGFR3; FGFR1-FGFR3; PDGFR; C-KIT; and RET | Lenvatinib | I Ib/II | Monotherapy in advanced melanoma In advance melanoma in combination with pembrolizumab | 17.2 48 | [62] [63] |
C-KIT inhibitor | Imatinib, Nilotinib, Dasatinib | II | Studied in mucosal, acral, and chronically sun-damaged melanomas | 23.3–26.2 | [64,65,66] |
IGF-1 inhibitor | Linsitinib | I | In combination with erlotinib in solid tumors | 1/1 | [67] |
EGF inhibitor | Gefitinib, Erlotinib | II, I | Minimal clinical efficacy as a single-agent therapy for unselected patients with metastatic melanoma. In combination with pictilisib (PI3K inhibitor) in solid tumors | 3.5–4 | [68,69] |
VEGF inhibitor | Bevacizumab | II | In combination with dacarbazine for the treatment of unresectable/metastatic melanoma In combination with temozolomide as the first line of treatment metastatic uveal melanoma | 18.9 0 | [70] [71] |
MEK inhibitor | Pimasertib Selumetinib | II I | Monotherapy in NRAS-mutated melanoma Monotherapy in comparison to temozolamide in chemo-naive stage unresectable III/Vmelanoma | 23 5.8 | [72,73,74] |
PI3K/mTOR dual inhibitor | Voxtalisib | Ib | Tested in combination with pimasertib in melanoma patients with genetic alteration in PTEN, BRAF, NRAS, KRAS, PI3KCA, ERBB1/2, RET, MET, KIT, GNAQ, GNA11, but with limited antitumor activity and tolerance | 6 | [75] |
PI3K inhibitor | Pictilisib | I | In combination with erlotinib in solid tumors or alone | 3.5–22 | [68,76] |
mTOR inhibitor | Everolimus | I | In combination with VEGFR kinase inhibitor (vatalanib) for patients with advanced solid tumors | 12.9 | [77] |
Temsirolimus | II | Tested in combination with sorafenib Clinical activity of combination therapy with temsirolimus plus bevacizumab, which may be greater in patients with BRAF wild-type melanoma | 5 17.7 | [78,79] | |
AKT inhibitor | Uprosertib (GSK2141795) | I | In combination with trametinib in patients with advanced BRAF wild-type melanoma and triple-negative breast cancer | <5 | [80] |
AKT inhibitor | Afuresertib | I | In combination with the MEK inhibitor trametinib in patients with solid tumors and multiple myeloma | 5 | [81] |
Wnt inhibitor | Vantictumab (OMP-18R5) | NA | Have shown antitumor growth in xenograft models, particularly in combination with standard chemotherapeutic agents, have not reached clinical trial | NA | [82] |
LGK974 | I | Monotherapy or in combination with PDR001 in patients with solid tumors (recruiting) | NA | NA | |
IKK inhibitor | BMS-345541 | NA | A proposed target drug but have not reached clinical trial | NA | [83] |
MITF promoter: HDAC inhibitors | Panobinostat | I | Tested in patients with metastatic melanoma | 0 | [84] |
CDK4/6 inhibitor | Palbociclib | II I/II | Monotherapy in patients with advanced acral lentiginous melanoma with CDK pathway gene aberrations (CDK4 or/and CCND1 amplification or/and CDKN2A loss) In combination with vemurafenib in BRAFV600-mutated advanced melanoma patients harboring CDKN2A loss and RB1 expression | 20 27.8 | [85] |
CDK4/6 inhibitor | Abemaciclib | NA | Effective in BRAF-resistant melanoma cells, preclinical data | NA | [86] |
NTRK inhibitors | Selitrectinib (BAY 2731954, LOXO-195); Repotrectinib | NA | The second generation of NTRK designed to address on-target resistance, preclinical data on ROS1-, NTRK1-3-, or ALK-rearranged malignancies | NA | [87,88] |
ALK inhibitors | Ceritinib Crizotinib | NA I | In vivo and in vitro studies showed that mucosal melanomas expressing EML4-ALK fusions are sensitive to ALK inhibitors Crizotinib in combination with vemurafenib in advanced BRAF-mutated tumors, mostly melanoma | 11 29 | [89] [90] |
SF3B1 inhibitors | E7107 | I | Monotherapy in solid tumors | 0 | [91,92] |
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Teixido, C.; Castillo, P.; Martinez-Vila, C.; Arance, A.; Alos, L. Molecular Markers and Targets in Melanoma. Cells 2021, 10, 2320. https://doi.org/10.3390/cells10092320
Teixido C, Castillo P, Martinez-Vila C, Arance A, Alos L. Molecular Markers and Targets in Melanoma. Cells. 2021; 10(9):2320. https://doi.org/10.3390/cells10092320
Chicago/Turabian StyleTeixido, Cristina, Paola Castillo, Clara Martinez-Vila, Ana Arance, and Llucia Alos. 2021. "Molecular Markers and Targets in Melanoma" Cells 10, no. 9: 2320. https://doi.org/10.3390/cells10092320
APA StyleTeixido, C., Castillo, P., Martinez-Vila, C., Arance, A., & Alos, L. (2021). Molecular Markers and Targets in Melanoma. Cells, 10(9), 2320. https://doi.org/10.3390/cells10092320