Melanoma: Molecular genetics, metastasis, targeted therapies, immunotherapies, and therapeutic resistance

Abstract

Cutaneous melanoma is a common cancer and cases have steadily increased since the mid 70s. For some patients, early diagnosis and surgical removal of melanomas is lifesaving, while other patients typically turn to molecular targeted therapies and immunotherapies as treatment options. Easy sampling of melanomas allows the scientific community to identify the most prevalent mutations that initiate melanoma such as the BRAF, NRAS, and TERT genes, some of which can be therapeutically targeted. Though initially effective, many tumors acquire resistance to the targeted therapies demonstrating the need to investigate compensatory pathways. Immunotherapies represent an alternative to molecular targeted therapies. However, inter-tumoral immune cell populations dictate initial therapeutic response and even tumors that responded to treatment develop resistance in the long term. As the protocol for combination therapies develop, so will our scientific understanding of the many pathways at play in the progression of melanoma. The future direction of the field may be to find a molecule that connects all of the pathways. Meanwhile, noncoding RNAs have been shown to play important roles in melanoma development and progression. Studying noncoding RNAs may help us to understand how resistance - both primary and acquired - develops; ultimately allow us to harness the true potential of current therapies. This review will cover the basic structure of the skin, the mutations and pathways responsible for transforming melanocytes into melanomas, the process by which melanomas metastasize, targeted therapeutics, and the potential that noncoding RNAs have as a prognostic and treatment tool.

Keywords: BRAF inhibitors; Checkpoint inhibitors; Drug resistance; Immunotherapy; Melanoma; Melanoma metastasis; Skin cancer; Targeted therapy; Therapeutic resistance.

Figure 1

The structure and major components of the skin and gross melanoma lesions. (A) The skin consists of the cellular components of the three main layers, in addition to the five sublayers of the epidermis. Melanocytes are located in the stratum basale. (B) The locations and representative gross lesions of the three major subtypes of melanoma.

Figure 2

The epidemiology of melanoma. (A) The schematic representation of the breakdown percentage of clinical cases for each subtype of melanoma. (B) The anatomical locations of primary melanomas in men (a) and women (b). The illustrations were inspired by BioRender.

Figure 3

The progression and pathologic staging of melanoma. Melanoma originates from its initial location in the stratum basale in Stage 0/1 disease and progresses to distant metastatic sites like the lungs in Stage 4 disease. The illustrations were inspired by BioRender.

Figure 4

The components of the mitogen activated protein kinase (MAPK) pathway. The signaling cascade begins with the binding of a mitogen or growth signal on a cell surface receptor. This binding process allows RAS to exchange GTP for GDP, thus continuing the phosphorylation cascade in the cytoplasm until ERK translocates into the nucleus. The illustrations were inspired by BioRender.

Figure 5

Crosstalk of major signaling pathways in melanoma metastasis. The interactions of several different signaling pathways, such as RAS/BRAF/MAPK pathway, PI3K/AKT/mTOR pathway, and β-catenin pathway are frequently involved in melanoma metastasis. Several of the components of the MAPK signaling pathway that is responsible for the transformation of melanocytes also play key roles in the melanoma metastasis. The illustrations were inspired by BioRender.

Figure 6

Targeted therapies and resistance for melanoma. (A) This panel depicts the major players in the MAPK signaling pathway along with two drugs used to inhibit the pathway. Vemurafenib is a RAF inhibitor, while Trametinib is an MEK inhibitor. (B) Combination therapy and targeted therapy resistance. BRAF and MEK inhibitors can be used together to overcome the resistance to BRAF inhibitors. However, tumors can use other mechanisms to escape BRAF/MEK inhibitor treatment, including up-regulating RAS and/or PI3K-AKT pathways. Some tumor cells have mutations in RAS, RAF, or MEK that allow them to escape canonical BRAF/MEK inhibitor treatment, while others are able to grow and proliferate due to stromal cells that secrete high levels of HGH (see the text). The illustrations were inspired by BioRender.

Figure 7

Molecular immunology of immunotherapies for melanoma. Naïve T cells can be activated by interacting with dendritic cells (DC) through T-cell receptor (TCR), which is inhibited by B7/CTLA-4 interaction. Activated T cells launch immune attack on melanoma cells, which can be inhibited by PD-L1/PD-1 interaction. Therefore, targeted immunotherapeutic antibodies have been developed to inhibit CTLA-4, PD-L1 and/or PD-1 to treat melanoma and other types of cancer. The illustrations were inspired by BioRender.