An overview of benefits and risks of chronic melanocortin‐1 receptor activation

Abstract

The melanocortin‐1 receptor (MC1R) is a G protein‐coupled receptor that plays a pivotal role in human skin pigmentation, melanin synthesis, redox homeostasis and inflammation. Loss‐of‐function MC1R variants suppress G protein‐coupled receptor coupling or cell surface expression leading to a decrease in adenyl cyclase activation and intracellular levels of cyclic adenosine monophosphate. Chronic activation of MC1R can occur in certain medical conditions such as Addison's disease and physiologic states such as pregnancy melasma. MC1R activation is more commonly caused by environmental exposure to ultraviolet (UV) radiation. Approved pharmacologic melanocortin agonists that activate MC1R signalling in a targeted manner or as a bystander effect have recently become available for erythropoietic protoporphyria, sexual desire disorders, monogenic obesity and syndromic obesity. Further, small peptide analogues of α–melanocortin‐stimulating hormone, human MC1R selective agonists, are photoprotective, decreasing the adverse impact of UV radiation (a primary risk factor for skin cancer) and are being investigated as potential chemoprevention strategies. MC1R activation through induction of UV‐protective skin pigmentation increased DNA repair, and control of aberrant cell growth may reduce the risk of melanoma but importantly does not prevent melanoma particularly in individuals with risk factors and regular skin examination remains critical in high‐risk individuals.

Thinner line widths indicate typical physiologic signalling, thicker lines indicate increased signalling and red x's indicate suppressed signalling. Larger eumelanin and pheomelanin ovals indicate higher protein synthesis, while smaller ovals indicate lower protein synthesis. Eumelanin and pheomelanin protein synthesis levels as compared to levels at MC1R basal activity are indicated as lower or higher by ‘<’ and ‘>’, respectively.

Key points.

Why Was the Study Undertaken?

Although the structure of the melanocortin‐1 receptor (MC1R) and its variants in melanoma risk have been previously described, the impact of constitutive and pharmacologic activation of MC1R have not been extensively covered.

What Does this Study Add?

Long‐term activation of MC1R, either physiologically or pharmacologically, has not been associated with increased incidence of melanoma, whereas loss‐of‐function variants in MC1R have been associated with an increased risk of melanoma.

What Are the Implications of this Study for Disease Understanding and/or Clinical Care?

Although chronic MC1R activation has demonstrated benefits, it does not serve as a complete preventative measure for melanoma. Patients who receive melanocortin receptor pharmacotherapies should continue to limit ultraviolet radiation exposure and have regular dermatologic surveillance as part of standard, dermatologic health practice.

INTRODUCTION AND OVERVIEW OF MELANOCORTIN‐1 RECEPTOR STRUCTURE AND FUNCTION

Melanocortin receptor family

The melanocortin system is composed of multiple signalling hormones, ligands and associated melanocortin receptors (MCRs; melanocortin‐1 receptor [MC1R] through MC5R) that are involved in many biologic pathways and bodily functions. ¹ , ² , ³ , ⁴ MC1R plays a pivotal role in human skin pigmentation, melanin synthesis, DNA repair and inflammation (Figure 1). ¹ , ² , ³ , ⁵ , ⁶ , ⁷ , ⁸ , ⁹ MC2R, expressed in the adrenal cortex, is involved in steroidogenesis. ² , ³ , ⁴ Adrenocorticotropic hormone (ACTH) binds to MC2R located on the surface of adrenal zona fasciculata cells, thereby producing cortisol. ¹⁰ MC3R and MC4R are expressed in the central nervous system and are pivotal in the regulation of hunger, satiety, and overall energy homeostasis. ³ , ⁴ , ¹¹ , ¹² MC3R has been linked to timing of sexual maturation and linear growth. ¹³ Some studies have reported the association between MC4R and sexual function. ² , ³ MC5R has been linked to exocrine function, especially of the sebaceous glands. ² , ³ , ⁴

FIGURE 1.

Melanocortin signalling for melanin production and anti‐inflammatory effects in melanocytes. ⁵ , ⁶ , ⁷ , ⁸ , ⁹ α‐MSH, α–melanocortin‐stimulating hormone; AC, adenylyl cyclase; cAMP, cyclic adenosine monophosphate; ACTH, adrenocorticotropic hormone; CREB, cAMP response element–binding protein; DCT, dopachrome tautomerase; IκBα, NF‐κB inhibitor α; MC1R, melanocortin‐1 receptor; MITF, microphthalmia‐associated transcription factor; NF‐κB, nuclear factor κB; PC1, proprotein convertase 1; PC2, proprotein convertase 2; PKA, protein kinase A; POMC, proopiomelanocortin; ROS, reactive oxygen species; TNFα, tumour necrosis factor α; TNFRI, tumour necrosis factor receptor type I; TYR, tyrosinase; UV, ultraviolet.

MC1R and pigmentation

MC1R is a 7‐transmembrane G protein‐coupled receptor expressed on the cell membrane of melanocytes that regulates melanocyte proliferation, melanin pigment synthesis, melanocyte differentiation and ultraviolet (UV) radiation sensitivity. ⁴ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ UV radiation is a natural inducer of MC1R expression and physiologic activation. ⁴ The high‐affinity MCR agonists, α–melanocyte‐stimulating hormone (α‐MSH) and ACTH are endogenous physiologic ligands that can activate MC1R. UV irradiation of skin induces p53 within the epidermis and directly upregulates expression of the precursor protein proopiomelanocortin (POMC). POMC is subsequently cleaved by prohormone convertase 1 to produce ACTH; prohormone convertase 2 then cleaves ACTH to generate α‐MSH. ³ , ⁴ , ¹⁴ , ¹⁹ , ²⁰ For biologic activation, α‐MSH is further processed by C‐terminal carboxypeptidase, α‐amidating monooxygenase and N‐acetyltransferase. ¹⁹ POMC‐derived peptides including ACTH, α‐MSH and β‐endorphin are generated in the skin, especially in keratinocytes and melanocytes. ¹⁴ α‐MSH is also produced in the hypothalamus of adults but not in the pituitary gland. ³ , ²¹ The endogenous ligand α‐MSH activates MC4R, a key receptor in the melanocortin‐MC4R pathway, which is the primary pathway in the brain that mediates energy expenditure, hunger, and consequently, body weight. ²²

α‐MSH also stimulates MC1R, and MC1R signalling can lead to the synthesis of melanin pigments: a dark brown/black UV radiation‐blocking pigment (eumelanin) and a yellow/red pigment (pheomelanin). ¹⁴ , ²³ The balance of eumelanin and pheomelanin determines skin and hair colour. ²⁴ When the skin is exposed to UV radiation and MC1R is activated by engagement with its newly synthesized ligand α‐MSH, the balance of melanin synthesis switches within melanocytes towards eumelanin. ⁵ , ⁸ Increased eumelanin production leads to darkening of the skin and pre‐existing nevi (i.e. benign skin growths formed by a cluster of melanocytes). ² , ⁸ , ²⁵

Anti‐inflammatory and immunomodulatory effects of MC1R activation

Eumelanin is photoprotective because it resists photodegradation, shields skin from UV radiation and scavenges reactive oxygen radicals. ²³ Pheomelanin, a potential independent risk factor for melanoma, can amplify reactive oxygen species production and oxidative DNA damage. ²⁶ , ²⁷ , ²⁸ α‐MSH has indirect antioxidative effects in melanocytes by regulating catalase and antioxidant response transcription factors such as nuclear factor κB (NF‐κB) and NF‐E2–related factor 2 (Nrf2). ¹⁹ , ²⁹ , ³⁰ α‐MSH inhibits activation of NF‐κB, a master regulator of inflammation by increasing intracellular levels of cyclic adenosine monophosphate (cAMP). Elevated levels of cAMP prevent degradation of NF‐κB inhibitor α, the inhibitory subunit of NF‐κB, thereby preventing p65 subunit translocation. ¹⁹ UV radiation‐induced down‐regulation of Nrf2 and the Nrf2‐dependent genes HMOX1, GCLC and GSTP1 is prevented or even overcorrected by α‐MSH. Of note, oxidized α‐MSH is unable to rescue suppression of Nrf2‐ and Nrf2‐dependent gene expression; therefore, this antioxidative mechanism may occur through the MC1R pathway. ²⁹ UV radiation can lead to genotoxic stress from the generation of cyclobutene pyrimidine dimers, 6–4 photoproducts and 7,8‐dihydro‐8‐oxoguanine, resulting in DNA damage, including DNA breaks. ³⁰ , ³¹ , ³² α‐MSH–mediated MC1R activation increases catalase and ferritin, improving cellular antioxidant status and mitigating oxidative DNA damage. ³⁰ Given that pheomelanin incorporates cysteine into its structure, it may generate reactive oxygen species through depletion of glutathione stores. ²⁷ α‐MSH has been shown to protect against UV radiation‐induced genotoxic stress and reduce cell death mediated by caspase‐3, H₂O₂, tumour necrosis factor α (TNF‐α) and interleukin‐1β (IL‐1β). ¹⁹

Along with regulating pigmentation, MC1R signalling is a key mediator of DNA repair and reactive oxygen species regulation following UV‐induced damage. ⁵ , ⁹ , ³³ , ³⁴ Studies have demonstrated that MC1R signalling promotes UV‐induced DNA repair via nucleotide excision repair pathways independent of melanin pigmentation. ⁹ , ³⁵ , ³⁶ , ³⁷ In an in vitro study, α‐MSH demonstrated antiapoptotic effects following UV radiation in human melanocytes and keratinocytes that were independent of melanin content via nucleotide excision repair of cyclobutene pyrimidine dimer DNA lesions. ³⁵ Conversely, loss‐of‐function MC1R variants can lead to compromised DNA repair response and increased apoptosis because expression of protective genes is reduced. ³³ , ³⁷

In addition to having a role in pigmentation and DNA repair, in vitro and in vivo studies have demonstrated that MC1R activation exhibits anti‐inflammatory and immunomodulatory properties (Figure 1). ² , ³⁸ , ³⁹ , ⁴⁰ Leukocytes and other cell types involved in inflammation express MC1R, which can mediate the immunomodulatory properties of melanocortins. ² , ³⁹ , ⁴⁰ Melanocortins, including α‐MSH, can stimulate the production of immunosuppressive factors and inhibit the production of proinflammatory factors. ² , ¹⁹ α‐MSH was initially demonstrated to suppress the well‐known proinflammatory cytokines interferon‐γ and TNF‐α and was later shown to suppress others such as IL‐1β, IL‐1, IL‐6, growth‐related oncogene α and lymphotactin. ¹⁹ The MC1R‐mediated anti‐inflammatory role of α‐MSH has also been shown to suppress allergen‐induced basophilic activation and cytokines including IL‐4, IL‐6 and IL‐13. ⁴¹ Further, α‐MSH induces expression of the immunosuppressive cytokine IL‐10 and exhibits further immunomodulatory effects through suppressing the expression of intercellular adhesion molecules and cell surface molecules including intercellular adhesion molecule 1, CD40, CD86 and ectopic major histocompatibility complex class I. α‐MSH can also suppress noncytokine proinflammatory mediators such as prostaglandins and nitric oxide. ¹⁹ In mice, α‐MSH has been shown to upregulate CD8⁺ T cells, reduce allergic contact sensitivity and reduce progressive tumour growth. ⁴²

LOSS‐OF‐FUNCTION MELANOCORTIN‐1 RECEPTOR POLYMORPHISMS

Population‐based studies have demonstrated that MC1R is highly polymorphic, with ~200 identified allelic variants to date, with an ~60% prevalence for any MC1R variant among individuals of European ancestry. ⁴ , ⁴³ , ⁴⁴ , ⁴⁵ Loss‐of‐function MC1R variants are associated with decreased eumelanin production, impaired tanning ability and UV radiation‐induced DNA damage in skin cells. ¹⁴ Loss of MC1R signalling can occur because of MC1R variants associated with key positions that reduce or block receptor function (i.e. activation of cAMP) via loss of G protein‐coupled receptor coupling or reduced cell surface expression. ⁴⁶ Activation of loss‐of‐function MC1R variants has also been shown to activate p38 mitogen‐activated protein kinase (MAPK), extracellular signal‐regulated kinase 1 and 2 (ERK‐1/2) and Akt pathways. ⁴⁷ , ⁴⁸ , ⁴⁹ , ⁵⁰ , ⁵¹

An early study of MC1R variants in humans by Valverde et al reported an association of specific variants with red hair colour, fair skin and impaired tanning response to UV radiation, with MC1R variants identified in 82% of patients with red hair. ⁵² Individuals with both biallelic and heterozygous MC1R variants demonstrate impaired tanning following UV radiation. ⁵³ , ⁵⁴ In a study comparing patients with and without cutaneous malignant melanoma, the frequency of specific MC1R variants was significantly higher in patients with melanoma versus the control population, with a 2.2‐fold increase in risk for those with one active variant and a 4.1‐fold increase for those with two variants. ⁵⁵ Although many variants affect the signalling ability of MC1R, the red hair colour variants D84E, R142H, R151C, R160W and D294H—which are associated with complete or partial loss of function of the MC1R—are especially associated with increased melanoma risk. ³³ , ⁵³ , ⁵⁶ , ⁵⁷ Mechanisms of loss of function of MC1R red hair colour variants include reduced receptor functional activity and reduced cell surface expression of the receptor. ⁵³

MELANOMA: AETIOLOGY, MECHANISMS OF DEVELOPMENT AND THE ROLE OF MELANOCORTIN‐1 RECEPTOR SIGNALLING

Melanomas are malignant tumours that arise from uncontrolled melanocyte proliferation (Figure 2, ⁵ , ⁷ , ⁸ , ⁵⁰ , ⁵⁸ , ⁵⁹ , ⁶⁰ , ⁶¹ , ⁶² , ⁶³ , ⁶⁴ , ⁶⁵ , ⁶⁶ ). Malignant melanoma accounts for most skin cancer‐related deaths. Sun exposure and UV radiation damage are the primary causes of melanoma, with most cases of melanoma (range, ~60%–85%) believed to be caused by excess UV radiation. ⁹ , ⁶⁷ , ⁶⁸ , ⁶⁹ UV radiation and the resulting DNA damage cause deleterious variants that drive the oncogenic process. ⁹ Both UVA and UVB radiation can lead to direct DNA damage, with UVB generating cyclobutene pyrimidine dimer formation and cell apoptosis and UVA damage promoting reactive oxygen species that induce direct DNA damage. ⁹ , ⁶⁸

FIGURE 2.

MC1R signalling pathway during basal physiologic (left), hyperactivation (middle) and loss of function with UV radiation (right) conditions. ⁵ , ⁷ , ⁸ , ⁵⁰ , ⁵⁸ , ⁵⁹ , ⁶⁰ , ⁶¹ , ⁶² , ⁶³ , ⁶⁴ , ⁶⁵ , ⁶⁶ Thinner line widths indicate typical physiologic signalling, thicker lines indicate increased signalling and red x's indicate suppressed signalling. Larger eumelanin and pheomelanin ovals indicate higher protein synthesis, while smaller ovals indicate lower protein synthesis. Eumelanin and pheomelanin protein synthesis levels as compared to levels at MC1R basal activity are indicated as lower or higher by ‘<’ and ‘>’, respectively. α‐MSH, α–melanocortin‐stimulating hormone; AC, adenylyl cyclase; cAMP, cyclic adenosine monophosphate; BRAF, B‐Raf proto‐oncogene, serine/threonine kinase; CREB, cAMP response element–binding protein; ERK‐1/2, extracellular signal–regulated kinase 1 and 2; MC1R, melanocortin‐1 receptor; MEK, mitogen‐activated protein kinase kinase; MITF, microphthalmia‐associated transcription factor; pAkt, phospho‐Akt; PI3K, phosphatidylinositol 3‐kinase; PKA, protein kinase A; PIP₂, phosphatidylinositol 4,5‐bisphosphate; PIP₃, phosphatidylinositol 3,4,5‐trisphosphate; RAS, rat sarcoma; ROS, reactive oxygen species; TYR, tyrosinase; UV, ultraviolet.

Melanoma development can have multifactorial causes, with driving contributions from the environment (i.e. UV radiation) and genetic predisposition. ⁶⁸ Seven of the nine most‐studied MC1R variants are positively associated with melanoma, while five and two of these variants are also positively associated with red hair and fair skin, respectively (Table 1, ⁷⁰ ). All of the most studied MC1R variants positively associated with red hair and/or fair skin were also positively associated with melanoma. ⁷⁰ In most cases, melanoma proliferation is under the constitutive activation of the MAPK signalling pathway. ⁷¹ Mutations in the proto‐oncogenes BRAF (50%–70%) and, to a lesser extent, NRAS (15%–30%) and KIT (2%–5%), are primarily responsible for MAPK activation in melanoma. ⁷¹ , ⁷² NF1 variants, which are typically loss‐of‐function variants, can also lead to dysregulation of the MAPK signalling pathway and account for an estimated 12%–18% of melanomas. ⁷³

TABLE 1.

Association of phenotype characteristics and melanoma in the most‐studied MC1R variants. ⁷⁰

MC1R variant	Variant association with
	Fair skin	Red hair	Melanoma
V60L	−	−	−
V92M	−	−	−
I155T	−	−	+
R163Q	−	−	+
D84E	−	+	+
R142H	−	+	+
R151C	−	+	+
R160W	+	+	+
D294H	+	+	+

Characteristics positively associated with a variant are denoted with ‘+’ and characteristics not positively associated with a variant are denoted with ‘–’.

The neoplastic transformation process requires additional genetic changes, namely telomerase reverse transcriptase overexpression or suppression of the retinoblastoma and/or p53 pathways. ⁷¹ A variant in the promoter of TERT is involved in ~70% of sporadic melanomas, and this variant is induced by UV radiation. ⁷¹ Variants in CDKN2A, an important tumour suppressor, have also been identified in 10%–40% of familial cases of melanoma. ⁷⁴ MC1R variants have also been associated with other pathways, including the MAPK, ERK and Akt pathways. ⁴⁹ , ⁵⁰ , ⁶⁵ , ⁷⁵ , ⁷⁶ Although there is evidence that hyperactivation of cAMP, ERK and Akt signalling can drive oncogenic transformation, these pathways have also been demonstrated to promote DNA damage response and mitigate oxidative stress and DNA damage. ⁴⁷ , ⁴⁹ , ⁵⁰ , ⁷⁵ , ⁷⁶ MC1R signalling may be protective by contributing to eumelanin production and preventing or reducing DNA genotoxicity and enhancing DNA repair mechanisms. ⁵ , ³⁰ , ⁷¹

While MC1R polymorphisms can increase phosphatidylinositol 3‐kinase signalling and senescence in melanocytes, hyperactivation of this pathway in melanocytes expressing BRAF V600E can lead to oncogenesis. ⁷⁷ However, UVB irradiation in transgenic mice with compromised MC1R signalling and conditional melanocyte‐specific Braf V600E expression led to the development of melanoma. Notably, inhibition of the depalmitoylation enzyme acyl‐protein thioesterase 2 led to delayed onset and lower rates of melanoma in mice expressing melanocyte‐specific zinc finger DHHC‐type palmitoyltransferase 13 and an MC1R variant. ⁷⁷ , ⁷⁸

There are also population‐based risk factors associated with melanoma. Globally, age‐standardized rates of melanoma incidence vary among regions, ranging from the highest in Australia and New Zealand (35.8 per 100,000 population) to the lowest in West Africa (0.33 per 100,000 population). ⁷⁹ Variations in melanoma incidence could be attributed to skin phenotype and excessive sun exposure potentially related to cultural and/or economic differences. ⁸⁰ , ⁸¹ Overall, men have a higher incident age‐standardized rate of melanoma than women. ⁷⁹ , ⁸² Notably, women have higher incidence in younger age groups and men have a higher incidence in older age groups. ⁸¹ However, an increased trend in incidence was observed in individuals aged ≥50 years, regardless of sex. ⁷⁹ The role of MC1R in other cancers is under investigation. Interestingly, MC1R expression and signalling has been associated with colon and breast cancer and may serve as an independent prognosis marker. ⁷⁶ , ⁸³ , ⁸⁴ , ⁸⁵

EXAMPLES OF CONDITIONS AND SITUATIONS OF CONSTITUTIVE MELANOCORTIN‐1 RECEPTOR ACTIVATION

Ultraviolet radiation

As discussed previously, UV radiation, such as sun exposure or tanning, induces α‐MSH and ACTH production and thus stimulates MC1R‐mediated eumelanin synthesis. ² , ⁴ Whereas UV‐associated radiation is a primary cause of DNA damage and melanoma, UV radiation‐induced MC1R activation can be protective against melanoma by enhancing DNA repair pathways (i.e. nucleotide excision repair), protecting against reactive oxygen species and promoting melanogenesis. ⁴ , ⁹ , ³⁰ , ³⁵ , ³⁶ , ³⁷ , ⁸⁶

Addison's disease

Addison's disease, or chronic primary adrenal insufficiency, is a rare endocrine disorder resulting in cortisol deficiency. Decreased cortisol levels cause decreased feedback to the hypothalamic–pituitary axis leading to increased secretion of ACTH, which contributes to skin and mucous membrane hyperpigmentation via MC1R activation. ⁶¹ Although an overall increase in mortality due to malignancies is observed in Addison's disease, no elevated risk of any skin cancer, including melanoma, has been reported in epidemiologic studies. ⁸⁷ One study followed 3299 patients with primary adrenocortical insufficiency for 40 years, determining that the standardized incidence ratio (SIR) for melanoma skin cancer was numerically less than expected (0.7; 95% confidence interval, 0.2–1.6), consistent with the eumelanin‐mediated protective effects of MC1R agonism, although a higher incidence of nonmelanoma skin cancer was reported (SIR, 2.1; 95% confidence interval, 1.3–3.1), along with higher incidences of oral cancer and male genital system cancer. ²³ , ⁸⁸ To our knowledge, no studies of primary adrenal insufficiency (and the associated chronic activation of MC1R) suggesting an association with increased incidence of melanoma have been published.

Pregnancy Melasma

Hyperpigmentation occurs in ~85%–90% of pregnant women, appears to be associated, at least in part, with increased expression and/or signalling of MC1R, and typically resolves post‐partum. ⁶⁴ Notably, increased levels of α‐MSH in plasma have been observed during the third trimester of normal pregnancy. ⁸⁹ During pregnancy, melanocytes may be sensitive to elevated levels of α‐ and β‐MSH, as well as oestrogen, progesterone and β‐endorphins, which likely stimulate melanin production. ⁶⁴ While skin folds and intertriginous areas may darken, the most commonly affected areas include the areolas, nipples, genitalia, axillae, periumbilical area and inner thighs. ⁶⁴ Further, the linea alba may darken, and acanthosis nigricans can develop. ⁶⁴ In a cohort of 2025 patients with melanoma, 156 (7.7%) had pregnancy‐associated melanoma; no significant difference in survival outcomes was observed between people developing pregnancy‐ and non–pregnancy‐associated melanoma. ⁹⁰

PHARMACOLGIC ACTIVATION OF MELANOCORTIN‐1 RECEPTOR

Approved Melanocortin pharmacotherapies

In addition to conditions and environmental factors that promote physiologic MC1R activation, there are also MC1R agonists and various other pharmacologic treatments that activate MC1R signalling that are commercially available and in development in the United States and/or European Union for indications including erythropoietic protoporphyria (EPP), sexual desire disorders and monogenic and syndromic obesity (Table 2, ⁶⁰ , ⁹¹ , ⁹² , ⁹³ , ⁹⁴ , ⁹⁵ , ⁹⁶ , ⁹⁷ , ⁹⁸ , ⁹⁹ , ¹⁰⁰ , ¹⁰¹ , ¹⁰² ). Various investigational MC1R‐targeting compounds are also in clinical development.

TABLE 2.

Approved melanocortin pharmacotherapies and melanocortin pharmacotherapies in development.

Pharmacotherapy	Indications or treatment population	Mechanism of action	Structure	MCR interactions	Common adverse events (≥10%)
Approved melanocortin pharmacotherapies
Afamelanotide 91 , 92 , 93	Approved to increase pain‐free light exposure in adults with a history of phototoxic reactions from erythropoietic protoporphyria	MC1R agonist	Linear 13‐amino acid peptide with the following structure: Ac‐Ser‐Tyr‐Ser‐Nle‐Glu‐His‐(D)Phe‐Arg‐Trp‐Gly‐Lys‐Pro‐Val‐NH2 • × CH3COOH	MC1R > MC3R > MC4R > MC5R > MC2R	Nausea and headache
Bremelanotide 60	Approved for acquired, generalized hypoactive sexual desire disorder in premenopausal women	Nonselective MCR agonist	Cyclic 7‐amino acid peptide with the following structure: Ac‐Nle‐cyclo‐(Asp‐His‐D‐Phe‐Arg‐Trp‐Lys‐OH) • × CH3COOH	MC1R > MC4R > MC3R > MC5R > MC2R	Nausea, flushing, injection site reactions a and headache
Setmelanotide 94 , 95 , b	Approved for treatment of obesity and control of hunger in adult and paediatric patients with specifics forms of monogenic or syndromic obesity due to variants in POMC, PCSK1 or LEPR variants and BBS	MC4R agonist	Cyclic 8–amino acid peptide with the following structure: Ac‐Arg‐Cys‐(D)Ala‐His‐(D)Phe‐Arg‐Trp‐Cys‐NH2 • × CH3COOH	MC4R > MC3R ≈ MC1R	Skin hyperpigmentation, injection site reactions, c nausea, vomiting, headache and spontaneous penile erection d
Melanocortin pharmacotherapies in development
Repository corticotropin injection 96 , 97 , 98	Adults with rheumatoid arthritis e	Nonselective MCR agonist	Mixture of adrenocorticotropic hormone analogues and other pituitary peptides	MC4R > MC3R > MC1R > MC2R > MC5R f	Infection, g cushingoid, irritability, diarrhoea, acne and convulsion h
PL‐8177 99 , 100	Adults with active ulcerative colitis	Selective MC1R agonist	Cyclic 7‐amino acid peptide	MC1R	NA
RM‐718 102 , b	Adult and paediatric patients with hypothalamic obesity	Highly selective MC4R agonist	7‐((3H‐indol‐3‐yl) methyl)‐19‐(2‐acetamido‐5‐guanidinopentanamido)‐13‐benzyl‐10‐(3‐guanidinopropyl)‐16‐(1‐hydroxyethyl)‐3,3‐dimethyl‐6,9,12,15,18‐pentaoxo‐1,2‐dithia‐5,8,11,14,17‐pentaazacyclohenicosane‐4‐carboxamide hydrochloride	MC4R > MC5R > MC3R > MC1R > MC2R	NA

α‐MSH, α–melanocyte‐stimulating hormone; BBS, Bardet–Biedl syndrome; MCR, melanocortin receptor; M1CR, MC1 receptor; NA, not applicable or not available.

^a Includes injection site pain, unspecified injection site reactions, erythema, hematoma, pruritus, haemorrhage, bruising, paresthesia and hypoesthesia.

^b Unpublished data, Rhythm Pharmaceuticals, Inc.; 2023.

^c Injection site reactions include injection site‐associated events of erythema, pruritus, oedema, pain, induration, bruising, reaction, swelling, haemorrhage, hypersensitivity, hematoma, nodule, discoloration, erosion, inflammation, irritation, warmth, atrophy, discomfort, dryness, mass, hypertrophy, rash, scar, abscess and urticaria.

^d Male patients.

^e Acthar Gel is indicated as monotherapy for the treatment of infantile spasms in infants and children age <2 years, exacerbations of multiple sclerosis in adults and may be used for the following disorders and diseases: rheumatic, collagen, dermatologic, allergic states, ophthalmic, respiratory and oedematous state.

^f Partial agonist.

^g Including candidiasis, otitis media, pneumonia and upper respiratory tract infections.

^h In the treatment of infantile spasms, other types of seizures/convulsions may occur because some patients with infantile spasms progress to other forms of seizures (e.g. Lennox–Gastaut syndrome). Additionally, the spasms sometimes mask other seizures, and once the spasms resolve after treatment, the other seizures may become visible.

Afamelanotide

Afamelanotide, the first and most studied synthetic α‐MSH analogue, is a nonselective melanocortin tridecapeptide that can bind and activate MC1R. ⁶³ , ¹⁰³ , ¹⁰⁴ The structure of afamelanotide, [Nle, ⁴ D‐Phe ⁷ ]‐α‐MSH (also referred to as NDP‐α‐MSH), is identical to physiologic α‐MSH, with the exception of two amino acids at positions 4 and 7. ⁶³ , ¹⁰⁴ Afamelanotide is a subcutaneous implant allowing for controlled release that is approved by the United States Food and Drug Administration (FDA) to increase pain‐free light exposure in adults with a history of phototoxic reactions from EPP and by the European Medicines Agency (EMA) to prevent phototoxicity in adults with EPP. ⁹¹ , ⁹² Following visible light exposure, patients with EPP experience severe, phototoxic‐related pain and consequently may dramatically limit their exposure to light. Therefore, this population may represent a low–UV‐exposed population in which to assess the impact of chronic MC1R agonism without the major risk factor of developing UV‐mediated melanoma. ⁶³

To date, 201 patients have been treated in a clinical setting. ¹⁰⁵ , ¹⁰⁶ In an open‐label, Phase 2 trial, 5 patients with solar urticaria received a single subcutaneous dose of afamelanotide, which resulted in increased melanin density and photosensitivity improvement, such as increased minimum urticarial dose and decreased weal area. An increase in pre‐existing nevi pigmentation was reported. ¹⁰⁷ Afamelanotide may also have an anti‐inflammatory effect in patients with mild‐to‐moderate acne vulgaris, as demonstrated by an open‐label, Phase 2 trial (n = 3) in which afamelanotide resulted in a decreased number of total and inflammatory acne lesions. ¹⁰⁸ In Phase 3 double‐blind randomized placebo‐controlled trials of 167 patients with EPP, melanocytic nevi were reported in 2 of 86 patients (4%) receiving afamelanotide and 1 of 81 patients (2%) receiving placebo. Mild hyperpigmentation occurred at the implant site in one‐third of the patients who received afamelanotide. No melanomas were reported in the afamelanotide group. ¹⁰⁶ In a placebo‐controlled study of 65 White individuals, melanin density was significantly increased in all those receiving 3 months of treatment with afamelanotide, which was accompanied by decreased thymine dimer formation (indicative of reduced DNA damage). ¹⁰⁹ In a longitudinal observational study of 115 patients with EPP treated with afamelanotide for up to 8 years, 2 patients reported a new melanocytic nevus, which appeared 2.5 years after the first dose of afamelanotide in 1 patient and 5 years after the first dose in the other patient. ¹⁰⁵ More than 1000 patients have been exposed to afamelanotide with no melanoma events reported, with many who receive continuous treatment for 5 years and some for >10 years. ⁹¹ , ¹¹⁰

Bremelanotide

Bremelanotide is a nonselective MCR agonist approved by the FDA for the treatment of acquired generalized hypoactive sexual desire disorder in premenopausal women. ⁶⁰ To date, 684 patients have been treated in a clinical setting. ¹¹¹ While bremelanotide is an agonist for all 5 MCRs, bremelanotide primarily acts through MC1R and MC4R. ⁶⁰ In Phase 3 placebo‐controlled trials of bremelanotide, 1% of individuals who received bremelanotide (n = 627) reported hyperpigmentation. ⁶⁰ During the open‐label periods of these trials, an additional 7 individuals receiving bremelanotide (1%; n = 684) experienced hyperpigmentation, 6 of whom had received placebo during double‐blind treatment. ¹¹¹ Two patients experienced melanocytic nevi; cases were mild and resolved in both patients, and only 1 case was considered possibly related to bremelanotide. No malignant melanomas or other cutaneous malignancies were reported in any of these studies. ¹¹¹

Setmelanotide

Setmelanotide is approved by the FDA, EMA and Medicines and Healthcare products Regulatory Agency for the management of obesity and approved by the EMA and Healthcare products Regulatory Agency for the control of hunger in patients with certain rare genetic forms of monogenic or syndromic obesity. ⁹⁴ , ⁹⁵ , ¹¹² Setmelanotide is an MCR agonist that acts primarily on MC4R but also activates MC1R with >20‐fold less activity than that for MC4R. ⁶² To date, 926 patients have been treated in a clinical setting (unpublished data, Rhythm Pharmaceuticals, Inc.; 2023). While setmelanotide partially acts on MC1R, only 56% of patients reported skin hyperpigmentation (i.e. tanning) during the first month of setmelanotide treatment at clinical doses (unpublished data, Rhythm Pharmaceuticals, Inc.; 2023). ¹¹³ , ¹¹⁴ , ¹¹⁵ , ¹¹⁶ Although comparisons between different studies are limited, the proportion of patients who experienced hyperpigmentation was greater than that among those treated with afamelanotide; the mechanism of this discrepancy is currently unknown (unpublished data, Rhythm Pharmaceuticals, Inc.; 2023). ¹⁰⁶ The observed hyperpigmentation is generally uniform and plateaus before returning to baseline within ~1 month of treatment discontinuation (data on file, Rhythm Pharmaceuticals, Inc.) ¹¹⁵ , ¹¹⁷ , ¹¹⁸ Some patients also experience darkening of pre‐existing nevi or development of new nevi (clinical trial setting, n = 1; real‐world setting, n = 66 [data on file, Rhythm Pharmaceuticals, Inc.; 2023]) and changes in hair colour. ¹¹⁵ , ¹¹⁷ , ¹¹⁸ , ¹¹⁹ Outcomes following long‐term exposure of setmelanotide were assessed in 2 patients with POMC deficiency who participated in a Phase 2, open‐label pilot study, followed by an open‐label extension study, with each receiving setmelanotide daily for a range of 6.8–7.2 years. Although these patients experienced changes in hair colour and darkening of nevi, no additional persistent treatment‐related adverse events associated with skin were observed. ¹¹⁹ , ¹²⁰

All patients receiving setmelanotide treatment, whether in the clinical or real‐world setting, are recommended to have a baseline dermatologic examination and regular follow‐up visits because of skin changes due to the increased pigmentation. ⁹⁵ Across the setmelanotide clinical program, 1 patient with Bardet–Biedl syndrome, fair skin (Fitzpatrick skin type II), freckling, nevi and a history of excessive sun exposure was diagnosed with stage pT1a melanoma after 3 years of continuous treatment (unpublished data, Rhythm Pharmaceuticals, Inc.) The lesion was excised for cure. A second patient on commercial therapy with Bardet–Biedl syndrome, fair skin (Fitzpatrick skin type II), and a skin examination revealing extensive chronic UV‐related damage who lived on an island close to the equator experienced increased pigmentation of the skin and existing melanocytic nevi and was diagnosed with stage pT1a superficial spreading melanoma after 6 months of setmelanotide treatment. In both cases, the individuals were at high risk of melanoma. These patients receive regular dermatologic examinations as recommended, which resulted in earlier melanoma diagnosis and timely excision (data on file, Rhythm Pharmaceuticals, Inc.).

Nonlicensed and investigational Melanocortin pharmacotherapies

Melanocortin pharmacotherapies in development

Several melanocortin pharmacotherapies are currently in development, including repository corticotropin injection, PL‐8177, RM‐718, PL‐8331 and PL‐5000 (data on file, Rhythm Pharmaceuticals, Inc.). ⁹⁶ , ⁹⁷ , ⁹⁹ , ¹⁰⁰ , ¹⁰¹ , ¹⁰² Details of these pharmacotherapies are included in Table 2.

Melanotan II

Melanotan II is a synthetic cyclic α‐MSH analogue that is a nonselective MCR agonist and is not approved for use in any therapeutic indication. ¹²¹ , ¹²² Melanotan II can be purchased online and is typically self‐administered by individuals seeking the cosmetic effects of MC1R activation with the intent of increasing skin pigmentation. ¹²¹ Melanotan II induces eumelanin synthesis through MC1R activation and exaggerates UV‐mediated tanning. ¹²³ Because melanotan II can cross the blood–brain barrier and is nonselective, it also activates the other MCRs, resulting in adverse events including fatigue, loss of appetite and penile erection. ¹²¹ , ¹²⁴ However, loss of appetite resulting in weight loss and increased libido by actions of melanotan II within the central nervous system are often welcome side effects for the purchasers of this ‘Barbie drug’. ¹²¹ , ¹²⁵ , ¹²⁶ As an unregulated ‘treatment’, melanotan II has the additional potential risks associated with unknown impurities and varied concentrations. ¹²¹ , ¹²⁵

There have been at least five reports of melanomas during or after melanotan II use. All individuals had other risk factors such as fair skin, excess sun exposure/tanning bed use and/or family history of melanoma. ¹²⁵ , ¹²⁷ , ¹²⁸ , ¹²⁹ , ¹³⁰ A 20‐year‐old woman with Fitzpatrick skin type II and a history of tanning bed use was diagnosed with melanoma on her left gluteal region 3 months after a 3‐week course of self‐administered melanotan II treatment. ¹²⁹ In one report of a 23‐year‐old White woman with red hair and a familial history of melanoma, three melanoma lesions were identified on the back, abdomen and right arm following 3 years of self‐administered melanotan II treatment. Genetic testing revealed heterozygous gene variants in MC1R and CDKN2A, a high‐risk melanoma‐associated gene. Multiple melanoma risk factors such as familial history, sun‐seeking behaviour and other genetic factors, including MC1R variants, may increase the risk associated with melanotan II. ¹²⁵ A 23‐year‐old woman with Fitzpatrick skin type II and a history of tanning bed use developed melanoma on a pre‐existing nevus on her left knee 4 months after seven weekly self‐administered melanotan II treatments. ¹³⁰ A 42‐year‐old woman with Fitzpatrick skin type III and a history of sun exposure and tanning bed use developed melanoma on a nevus on the abdomen 3 months after a 1‐week course of self‐administered melanotan II treatment. ¹²⁸ A 66‐year‐old male with Fitzpatrick skin type II developed melanoma in‐situ on his right mandibular angle after 4 weeks of self‐administered melanotan II treatment. ¹²⁷ Additional skin conditions, such as dysplastic compound nevus, have also been reported after melanotan II use. ¹³¹ Individuals should avoid the use of nonlicensed pharmaceutical agents, including melanotan II, and consult with a healthcare professional about the risks and benefits of such an unregulated purchase. Safety of this nonlicensed drug has not been proven and, because of the potential risks associated with melanotan II, thorough skin examinations may lead to an earlier diagnosis of melanoma or other skin diseases. ¹²⁸ , ¹³⁰

Small peptide analogues of α‐MSH

Peptides, or any polymer of amino acids, are classified by the number of amino acids they contain (e.g. tripeptides are composed of three amino acid residues and tetrapeptides are composed of four amino acid residues). The development of small peptide analogues of α‐MSH that are human MC1R selective agonists for topical application can allow for photoprotection and chemoprevention of skin cancers. ¹⁴ Tetrapeptide α‐MSH analogues have been shown to be more potent than endogenous α‐MSH in activating MC1R and have improved selectivity over NDP‐α‐MSH for MC1R. ¹⁰³ , ¹³² Compared with α‐MSH, tripeptide α‐MSH analogues are similarly effective in activating cAMP, inhibiting H₂O₂ formation and enhancing DNA repair. ¹³³ KdPT is an α‐MSH–related tripeptide derivative that is structurally similar to the three amino acid residues of the α‐MSH C‐terminal and amino acids 193–195 of IL‐1β. ¹³⁴ KdPT has potent anti‐inflammatory effects capable of suppressing IL‐β–induced NF‐κB activation and IL‐6 and IL‐8 expression. ¹⁹ KdPT is also able to attenuate the TNF‐α– and interferon‐γ–induced breakdown of transepithelial electrical resistance in models of intestinal inflammation. KdPT treatment significantly reduced the severity of dextran sodium sulfate‐induced colitis in IL‐1R–deficient mice and severity of piroxicam‐induced colitis in IL‐10–deficient mice compared with control phosphate‐buffered saline treatment. The same beneficial effect of KdPT treatment on dextran sodium sulfate‐induced colitis was not seen in MC1R‐deficient mice, which suggests a reduced capacity of KdPT to mitigate colitis in the absence of MC1R and a potential role of MC1R in the mechanism of action of KdPT. ¹³⁴ However, KdPT does not appear to bind to the MC1R and is not pigment inducing (i.e. melanotropic). ¹³⁵ A Phase 2 trial in patients with ulcerative colitis confirmed the anti‐inflammatory action of KdPT without any evidence for pigment induction as an adverse effect. ¹³⁶ In accordance with these in vivo observations, KdPT did not induce pigmentation in B16 melanoma cells in vitro, indicating that this tripeptide is not melanotropic and not a bona fide melanocortin. ¹³⁴ , ¹³⁵

Dersimelagon

Dersimelagon, an oral selective MC1R agonist, significantly inhibited skin fibrosis and lung inflammation when administered prophylactically and suppressed skin fibrosis development when administered as a therapeutic treatment in a bleomycin‐induced systemic sclerosis mouse model. ¹³⁷ , ¹³⁸ Further, dersimelagon suppressed the activation of inflammatory cells and inflammation‐related signals. ¹³⁷

Dersimelagon has been evaluated in a randomized, placebo‐controlled, Phase 2 trial in patients with EPP (n = 93) or X‐linked protoporphyria (n = 9). Following 16 weeks of dersimelagon treatment, the least‐squares mean difference from placebo in the change from baseline in mean daily time to the first prodromal symptom associated with sun exposure increased by ~1 hour (53.8 min for those who received 100 mg and 62.5 min for those who received 300 mg) compared with placebo. Hyperpigmentation was reported in 14 patients (21%) who received dersimelagon and no patients who received placebo. Melanocytic nevus was reported in 11 patients (16%) who received dersimelagon compared with 3 (9%) who received placebo. Melanoma was not reported as an adverse event in this study. ¹³⁹

SUMMARY AND CONCLUSIONS

Activation of MC1R in melanocytes results in increased eumelanin synthesis that shields against UV radiation, enhances DNA repair activity and increases antioxidant capacity. Increased skin pigmentation may be associated with a darkening of pre‐existing nevi. Long‐term activation of MC1R, either physiologically or pharmacologically, has not been shown to be associated with increased incidence of melanoma whereas loss‐of‐function variants in MC1R have been associated with an increased risk of melanoma. MC1R activation through induction of UV radiation‐protective skin pigmentation, increased DNA repair and control of aberrant cell growth may reduce the risk of melanoma but does not prevent the development of melanoma.

UV light exposure is the primary risk factor for the development of melanoma, and fair‐skinned individuals (Fitzpatrick ≤3) are at increased risk of melanoma independent of pharmacologic activation of MC1R; these individuals should have regular close dermatologic surveillance. Because the pigment‐enhancing effect of MC1R agonism may unmask a pre‐existing melanoma, careful surveillance in this setting may allow for an earlier diagnosis with a greater chance of curative resection. Although dark‐skinned individuals may be at lower risk of melanoma, and chronic stimulation of MC1R with proportionally more eumelanin secretion may be further protective, it does not prevent melanoma. Patients who receive MCR pharmacotherapies should continue to limit UV radiation exposure and have regular dermatologic surveillance, which can lead to early identification of pre‐existing melanoma.

Although chronic MC1R activation has demonstrated benefits, such as UV‐protective skin pigmentation, enhanced DNA repair, regulation of aberrant cell growth and reduction of melanoma risk, it does not serve as a complete preventive measure, especially in individuals with melanoma risk factors. Regular skin examination remains crucial for those at high risk of developing melanoma, including those with fair skin, excess sun exposure/tanning bed use and/or family history of melanoma.

FUNDING INFORMATION

Writing and editorial assistance for the preparation of this article was provided under the direction of the authors by MedThink SciCom and funded by Rhythm Pharmaceuticals, Inc.

CONFLICT OF INTEREST STATEMENT

MB, CR and SF have no conflicts of interests to disclose. At the time of first submission, SM was a full‐time employee of Rhythm Pharmaceuticals, Inc. and held company‐awarded stocks or stock options. KC is primary investigator for setmelanotide trials in the obesity field.

ETHICS STATEMENT

Not relevant because this is a review article and did not involve any human or animal research.

Böhm M, Robert C, Malhotra S, Clément K, Farooqi S. An overview of benefits and risks of chronic melanocortin‐1 receptor activation. J Eur Acad Dermatol Venereol. 2025;39:39–51. 10.1111/jdv.20269

DATA AVAILABILITY STATEMENT

Data sharing not applicable to this article as no data sets were generated or analysed during the current study.