Molecular Susceptibility and Treatment Challenges in Melanoma
Abstract
:1. Introduction
2. Genetics of Melanoma
3. Understanding the Genetic Changes That Fuel Treatment Resistance: The Melanoma Code
3.1. BRAF and MEK Inhibitors
3.2. Genetic Background of Therapy Resistance
Mutation | Mechanism |
---|---|
BRAF gene amplification and splicing | The BRAF gene was amplified, which significantly increased the expression (BRAF protein) and prompted the reactivation of ERK when BRAF inhibitors were present. The production of shortened BRAF proteins, which contain the kinase domain but lack the RAS-binding N-terminus region, can result through alternative splicing and form homodimers that are resistant to BRAF inhibitors [59,68,70,73,74,75]. |
BRAF secondary mutations | Patients who were resistant to BRAF inhibitors showed secondary mutations in L505H or the single-nucleotide alteration V600E. The V600E mutation raises BRAF kinase activity and results in MEK inhibitor cross-resistance [57,76]. |
MEK1/2 mutations | Without BRAF activation, MEK1/2 mutations could restart downstream ERK signaling [73,74,75,77]. |
Receptor interaction proteins, RTKs, or membrane receptors are upregulated | Through the stimulation of parallel pathways or by directly inducing the RAS pathway, overexpression or hyperactivation of membrane receptors/RTKs, which is partially mediated by MITF copy gain, may promote acquired resistance [69,70,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92]. |
Inconsistencies with in PI3K-AKT cascade | PI3K and AKT-activating mutations enhance AKT signaling by promoting anti-apoptotic signals and elevating expression of essential proliferative genes, enabling survival signals independent of BRAF [70,93,94,95,96,97,98,99,100,101,102]. |
3.3. MicroRNA and Melanoma
4. Mechanisms of Resistance to Immune Therapy/Checkpoint Inhibitors
Drivers | Immune-Evasion Mechanism | References |
---|---|---|
Primary resistance | ||
VEGF and ANG2 overexpression | TME infiltration by TILs | [135] |
CXCR3 | Restores the cytotoxicity of CD8+ in TME | [136,137] |
TMB | Regulates immunotherapy response | [138,139,140,141] |
IL-6 and IL-10 levels in TME | Impairs DC maturation | [142,143,144] |
Acquired resistance | ||
B2M | Regulates MHC class I-mediated tumor antigen presentation in tumor lesions | [127,145] |
JAK1 | Regulates transcription of the IFN- γ-inducible genes and T-cell infiltration | [146] |
EZH2 |
| [147,148] |
KDM5B | Overexpression of SETDB1 (H3K9 methyl transferase) | [149,150,151,152] |
SETDB1 | Regulates the expression of immune-related gene clusters that encode MHC I antigens | [134,150] |
HDAC6 | Regulates IL-10 and PD-L1 expression | [148] |
FTO | Regulates PD-1 expression | [153] |
LAG3 | Regulates the activity of T-cells | [154,155,156,157] |
TIM-3 | Regulates the activity of T-cells | [134,158,159] |
SK1 | Regulates S1P, which in turn regulates lymphocyte trafficking and differentiation | [160,161] |
FCRL6 | Regulates cytotoxic NK cells and effector T-cells | [162] |
NLRP3 | Regulates the recruitment into tumor tissues | [163] |
Microbiome | Regulates macrophage polarization and DCs activation and CD8+tumor recruitment | [164,165,166,167,168] |
4.1. Clinical Predictors of Immune Therapy in Metastatic Melanoma
4.2. Predictive Features of Response to Immune Checkpoint Blockade (ICB)
5. Gender Differences in Melanoma
6. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Melanoma Subtype | Location |
---|---|
Melanomas arising in sun-exposed skin | |
Low-CSD * melanoma/superficial spreading melanoma | Trunk or extremities |
High-CSD * melanoma (including lentigo maligna melanoma and high-CSD * nodular melanoma) | Head and neck region |
Desmoplastic melanoma | Head and neck, trunk, or extremities |
Melanomas developing in shielded areas or without known etiological associations with UV radiation exposure | |
Malignant Spitz tumor (Spitz melanoma) | Head and neck, trunk, or extremities |
Acral melanoma | Acral sites |
Mucosal melanoma | Mucosae |
Melanoma arising in congenital nevus | Trunk and proximal parts of the limbs, scalp, or neck |
Melanoma arising in blue nevus | Scalp, extremities, or trunk |
Uveal melanoma | Eyes |
Gene Name | Gene Symbol | Frequency (%) | Most Commonly Reported Mutations | Pathway | Function |
---|---|---|---|---|---|
Somatic GOF/Activating mutations | |||||
Braf Proto-Oncogene, Serine/Threonine Kinase | BRAF | 40–60 | V600E V600K V600D | MAPK signaling | Cell proliferation and survival |
Neuroblastoma RAS Viral Oncogene Homolog | NRAS | 15–25 | G13R G12D Q61H Q61R Q61K Q61L G12S | MAPK/PI3K signaling | Cell proliferation, differentiation, and survival |
Ras-related C3 Botulinum Toxin Substrate 1 | RAC1 | ~9 | P29S P29L P34S P159L V14E E31D | MAPK signaling | Cell proliferation and migration |
KIT proto-oncogene receptor tyrosine kinase | KIT | 10 | L576P K642E V559A N822K N822I S451C G226W P36Q | MAPK/PI3K and JAK/STAT signaling | Cell proliferation and survival |
Telomerase reverse transcriptase | TERT | 40–50 | −57, T>G, Promoter mutation | Telomerase activity | Cell survival |
Mitogen-Activated Protein Kinase 1 and 2 | MAP2K1/2 | ~8 | K57N E203K F53I E203V Q278H F57V E207K G307C | MAPK signaling | Cell proliferation |
G Protein Subunit Alpha Q and 11 | GNAQ/11 | Rare | Q209P R300K K354N R183C H327R S268F R306L P262H R147S R300L | MAPK signaling | Cell proliferation |
Isocitrate Dehydrogenase 1 | IDH1 | ~8 | R132L R132C P33S | Metabolism of isocitrate | Cell proliferation and impaired differentiation |
Erb-b2 Receptor Tyrosine Kinase 2/4 | ERBB2/4 | 1/19 | R138W R190L H809N Q1200H G1056C P551H L403P G573D D150N E969K R196C P943S | Tyrosine kinases signaling | Cell proliferation and survival |
Kirsten Rat Sarcoma Viral Oncogene Homolog, GTPase | KRAS | 1–2 | G13D G12D | GTPase activity | Cell proliferation and survival |
Splicing Factor 3b Subunit 1 | SF3B1 | 10–20 | R625C R1297C R625H P228S P465S P370L | Alternative splicing | Tumorigenesis |
Somatic LOF/deleterious mutations | |||||
Neurofibromin 1 | NF1 | 10–15 | Q347 * W1952 * W336 * V341Cfs * 12 Q2239 * R2517 * | MAPK/PI3K signaling | Cell proliferation, differentiation, and survival |
Phosphatase and tensin homolog | PTEN | 4–8 | C211 * D19N V217I | PI3K signaling | Apoptosis, cell survival, and immune evasion |
Tumor protein p53 | TP53 | 15 | E294 * | Caspase3, FAS, and CTL-mediated apoptotic pathways | Cell cycle progression, DNA repair, and apoptosis |
RAS P21 Protein Activator 2 | RASA2 | ~5 | R551C | RAS signaling | Cell proliferation and migration |
Germline LOF/deleterious mutations | |||||
Cyclin-dependent kinase inhibitor 2A | CDKN2A | 10–30 | Exon 1 deletion Val22Profs * 46 Tyr44 * Trp15 * Ser12 * | RB pathway | Apoptosis and cell survival |
Cyclin-dependent kinase 4 | CDK4 | NA | R24C R24H | G1/S phase cell cycle checkpoint | Cell cycle progression |
Mutation | Frequency (%) |
---|---|
Cutaneous melanoma | |
BRAF | 50 |
NRAS | 15–20 |
KIT | 5 |
Acral melanomas | |
BRAF | 15 |
NRAS | 15 |
KIT | 15 |
Mucosal melanomas | |
KIT | 15 |
Uveal melanomas | |
GNAQ/GNA11 | >90 |
Spitz melanoma | |
BRAF | 37 |
NRAS | 18 |
NF1 | 11 |
NRAS Mutation | Non-NRAS Mutations | |
---|---|---|
Anti-PD-1/PD-L1 (n = 48) | ||
ORR | 64% | 30% |
CBR | 73% | 35% |
Ipilimumab (n = 169) | ||
ORR | 19% | 11% |
CBR | 42% | 19% |
first-line immune therapy | ||
(Kaplan–Meier analysis)—median duration | ||
PFS | 4.1 months | 2.9 months |
OS | 19.5 months | 15.2 months |
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Kolathur, K.K.; Nag, R.; Shenoy, P.V.; Malik, Y.; Varanasi, S.M.; Angom, R.S.; Mukhopadhyay, D. Molecular Susceptibility and Treatment Challenges in Melanoma. Cells 2024, 13, 1383. https://doi.org/10.3390/cells13161383
Kolathur KK, Nag R, Shenoy PV, Malik Y, Varanasi SM, Angom RS, Mukhopadhyay D. Molecular Susceptibility and Treatment Challenges in Melanoma. Cells. 2024; 13(16):1383. https://doi.org/10.3390/cells13161383
Chicago/Turabian StyleKolathur, Kiran Kumar, Radhakanta Nag, Prathvi V Shenoy, Yagya Malik, Sai Manasa Varanasi, Ramcharan Singh Angom, and Debabrata Mukhopadhyay. 2024. "Molecular Susceptibility and Treatment Challenges in Melanoma" Cells 13, no. 16: 1383. https://doi.org/10.3390/cells13161383