Molecular Susceptibility and Treatment Challenges in Melanoma

Abstract

Melanoma is the most aggressive subtype of cancer, with a higher propensity to spread compared to most solid tumors. The application of OMICS approaches has revolutionized the field of melanoma research by providing comprehensive insights into the molecular alterations and biological processes underlying melanoma development and progression. This review aims to offer an overview of melanoma biology, covering its transition from primary to malignant melanoma, as well as the key genes and pathways involved in the initiation and progression of this disease. Utilizing online databases, we extensively explored the general expression profile of genes, identified the most frequently altered genes and gene mutations, and examined genetic alterations responsible for drug resistance. Additionally, we studied the mechanisms responsible for immune checkpoint inhibitor resistance in melanoma.

Keywords: BRAF inhibitors; BRAF mutations; MEK inhibitors; immunotherapy; melanoma.

Figure 1

Classification of melanoma in association with sun exposure as per WHO 2018. The 2018 classification by WHO has categorized melanoma into different types based on sun exposure or sun damage. Created with BioRender.com.

Figure 2

Geographical distribution of co-occurring BRAF and NRAS mutations [31]. Co-occurrence of both BRAF and NRAS mutations specific to the various geographical areas, including Germany [32], USA [33,34], Italy [35], France [36], Brazil [37], Asia [38], Russia [39], China [40], Japan [41], and Australia [42].

Figure 3

Expression patterns of input genes in skin cutaneous melanoma: The heat map illustrates the expression profiles of various genes in primary and metastatic tumors in melanomas from the TCGA subset. Blue indicates lower expression, and red indicates higher expression on log 2 (TPM + 1) scale using UALCAN. The expression profile of genes associated with melanoma in melanoma patients was obtained from the UALCAN-UAB database [48]. The Y-axis represents the major genes associated with melanoma, and the X-axis represents the tumor type—primary tumor (n = 104) or metastatic tumor (n = 368). The image describes the differential expressions of the primary and the metastatic tumors. The above plot shows that RAC1, MAP2K2, and CDK4 consistently show high expression in all the patients, while TERT and ERBB4 show low expression. BRAF was found to have a lower expression, with log2(TPM + 1) values lying between 0 and 5, which is not consistent with the existing literature [50]. The expression profile of the other genes varies in each patient.

Figure 4

Overview of PI3K/AKT, RAS/MAPK, and JAK (Janus Kinases)/STAT (signal transducer and activator of transcription) signaling pathways promoting melanoma metastasis [114,115]. The MAPK, PI3K/AKT, and JAK/STAT pathways are all regulated by the receptor tyrosine kinases (RTKs) [113]. Created with BioRender.com.

Figure 5

Kaplan–Meier survival curves for OS and PFS. (A) OS and (B) PFS from ICI Cohort for BRAF (wild-type—WT) and BRAF-mutant (MT) cohorts. Improved OS and PFS trends for patients with BRAF mutations are depicted. Data were generated using the CAMOIP tool.