From genes to drugs: targeted strategies for melanoma

An Author Correction to this article was published on 12 October 2020

This article has been updated

Key Points

  • Oncogenic mutations in melanoma are increasingly well categorized and are not stand-alone events.

  • Several highly recurrent oncogenic mutations in melanoma occur within known signalling pathways. The most common of these is BRAF-V600E, which occurs in approximately 50% of melanomas.

  • Targeted therapies seek to inhibit functionally causative oncoproteins and have shown substantial promise in recent months.

  • Successful targeting of the BRAF-V600E or mutant KIT kinases has produced significant clinical responses in patients with advanced melanoma harbouring those mutations.

  • Targeted inhibition of the immune tolerance checkpoint with a blocking antibody approach has produced significant clinical responses in patients with advanced melanoma.

  • Permanent control of advanced melanoma remains uncommon for suppression of signalling or immune checkpoint targets. Improved strategies focus both on the development of new targeted therapeutics and on the analysis of combinations of these treatments.

Abstract

The past decade has revealed that melanoma is comprised of multiple subclasses that can be categorized on the basis of key features, including the clinical stage of disease, the oncogenic molecular 'drivers', the anatomical location or the behaviour of the primary lesion and the expression of specific biomarkers. Although exercises in subclassification are not new in oncology, progress in this area has produced both conceptual and clinical breakthroughs, which, for melanoma, are unprecedented in the modern history of the disease. This Review focuses on these recent striking advances in the strategy of molecularly targeted approaches to the therapy of melanoma in humans.

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Figure 1: Melanocyte differentiation: the MITF axis.
Figure 2: Immunomodulatory signalling.

Change history

  • 12 October 2020

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Acknowledgements

The authors apologize to the numerous colleagues whose important contributions could not be included in this Review owing to space limitations.

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Correspondence to David E. Fisher.

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Competing interests

K.T.F. serves as a consultant to GlaxoSmithKline and Roche/Genentech. F.S.H. has served as a consultant to Amgen and as a non-paid consultant for Bristol-Myers Squibb, Genentech and Novartis. He receives clinical research support from Bristol-Myers Squibb, Genentech, Novartis, Synta Pharmaceuticals and Pfizer. D.E.F. declares no competing financial interests.

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Glossary

Driver mutations

Sequence alterations in a cancer cell that influence the corresponding proteins to result in stimulation of cancerous activity within a cell.

Melanocyte

Melanin pigment-producing cell, usually located within the epidermis; the neoplastic transformation of this cell type gives rise to a nevus (benign) or melanoma (malignant).

Targeted therapy

A treatment designed to block a specific molecular species that is known to be functionally important.

Lineage-restricted oncogenes

Oncogenes the expression of which is limited to certain cell types.

Oncogene addiction

Tumour cell dependency on the molecular activity of an oncogene.

Mucosal

Referring to the cellular lining along internal cavities such as the gastrointestinal, genitourinary, oral or respiratory tracts.

Acral

Refers to hairless skin regions, such as palms and soles.

Solar elastosis

Sun-induced chronic damage to elastin and other connective tissue components within the dermis, typically seen in older people following chronic sun exposure.

Nevus

Benign pigmented lesion with features of senescence that can exhibit varying degrees of growth irregularity that may be concerning for transformation to melanoma. Melanocytic nevus refers to a benign pigmented lesion composed of nests of melanocytes.

G protein-coupled receptor

(GPCR). Family of cell surface transmembrane proteins that are regulated by extracellular ligands to modulate intracellular signalling via interactions with cofactors, the interaction of which is mediated by guanine nucleotide molecules.

Uveal melanoma

Melanoma arising in one of three anatomic locations within the eye: the iris, the choroid or the ciliary body.

Cell cycle checkpoints

Nodal points in the cell cycle that regulate the ability of the cyclin-dependent kinases to induce the progression through the phases of the cell cycle.

Humoral immune responses

Immune responses mediated by antibodies.

Pheresis

Removal of a blood component, as in removal of autologous dendritic cells (antigen-presenting cells), which may be used for adoptive transfer.

Hazard ratio

The effect of a variable on the hazard (or risk) of an event occurring.

Autologous

Pertaining to the host.

Freund's adjuvant

A water-oil emulsion (to which Mycobacterium Tuberculosis is sometimes added, complete Freund's adjuvant), which may potentiate immune responses when incorporated into a vaccine.

Immune checkpoint

Nodal point within signalling pathways that modulates the ability of the immune system to mount a robust response against a specific antigen or group of antigens.

Myeloid suppressor cells

Cells of the myeloid (granulocytic) lineage that inhibit immune responsiveness and may limit antitumour immunity.

Adoptive transfer

A therapeutic strategy consisting of the removal of cells (typically immune cells), ex vivo modulation (such as population expansion) and the re-infusion of cells.

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Flaherty, K., Hodi, F. & Fisher, D. From genes to drugs: targeted strategies for melanoma. Nat Rev Cancer 12, 349–361 (2012). https://doi.org/10.1038/nrc3218

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