PCSK9 May Serve as a Potential Therapeutic Target for Skin Melanoma

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A new study found proprotein convertase subtilisin/kexin type 9 (PCSK9) is associated with an increased cutaneous melanoma risk.

“The main discovery of this study is that PCSK9 may serve as a potential therapeutic target for skin melanoma,” investigators, led by Lusheng Miao, from the Third Affiliated Hospital of Guangzhou Medical University in China, wrote. “Our findings indicate that existing PCSK9 inhibitors, such as alirocumab and evolocumab, can influence melanoma by targeting LDL-related sites within the gene, thereby supporting the repurposing of these drugs.”

The rapid growth of melanoma, leading to skin cancer, can be attributed to dysregulated lipid metabolism. Although treatment options exist, the effectiveness of lipid-lowering drugs to treat cutaneous melanoma still needs to be determined due to conflicting research.

Some studies found a link between lovastatin use and reduced melanoma incidence, showing the treatment’s benefit.2 Another study found statins can enter melanoma metastasis and augment treatment in BFRAF inhibitor-resistant melanomas when used with other drugs.3 However, 1 study found the opposite—no significant association existed between statin use and melanoma risk.4

Due to mixed data, more research is needed to understand the association. Even if the treatments work for some patients with melanoma, other patients might not respond to the most available treatment methods due to specific genetic mutations.1

“This resistance, coupled with dosage limitations, underscores the necessity for combination therapy,” investigators added.

The study sought to assess the causal relationship between the outcomes of cutaneous melanoma with several lipid-lowering drug targets: 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR, targeted by statins, PCSK9 (targeted by alirocumab and evolocumab), and Niemann-Pick C1-like 1 (NPC1L1, targeted by ezetimibe).

The team leveraged variation data from the genome-wide association study of FinnGen, a large-scale genomics initiative examining 500,000 Finnish biobank samples and genetic variations with health data to learn more about disease mechanisms. To understand the relationship between cutaneous melanoma and lipid-lower drug targets, investigators used genetic strategies that affect the expression of drug target genes (analysis of polymorphisms) and those linked to low-density lipoprotein cholesterol levels to mimic the effects of lipid-lowering drugs.

After using Summary-data-based Mendelian Randomization and Inverse Variance Mendelian Randomization to assess the effectiveness of these lipid-lowering drugs, Miao and colleagues found a greater PCSK9 expression was associated with a greater cutaneous melanoma risk. The significant positive correlation between the 2 had an odds ratio of 1.44 with the Summary-data-based Mendelian Randomization (95% confidence interval [CI], 1.08 – 1.92; P = .011) and an odds ratio of 1.56 with the Inverse Variance Weighted Mendelian Randomization (95% CI, 1.10 – 2.23; P = .013). The findings signify inhibitors of PCSK9 may reduce the risk of this skin cancer.

The team applied a Bonferroni correlation with a P-value threshold of < .017 (0.05/3) to determine strong evidence of association. With this, the team did not observe any significant associations between cutaneous melanoma and either HMGCR (P = .039) or NPC1L1 (P = .906)

A limitation of the study the investigators pointed out was only focusing on cic-eQTLs without considering the potential effects of trans-QTLs which could have added bias to the results.

“This MR study indicates a potential causal connection between PCSK9 and heightened skin melanoma risk, with no association between HMGCR (target of statin drugs) and melanoma onset,” investigators concluded.

References

Miao L, Miao T, Zhang Y, Hao J. Association of lipid-lowering drug targets with risk of cutaneous melanoma: a mendelian randomization study. BMC Cancer. 2024;24(1):602. Published 2024 May 17. doi:10.1186/s12885-024-12366-8

Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998;279(20):1615–22.

de Groot E, Varghese S, Tan L, Knighton B, Sobieski M, Nguyen N, et al. Combined inhibition of HMGCoA reductase and mitochondrial complex I induces tumor regression of BRAF inhibitor-resistant melanomas. Cancer Metab. 2022;10(1):6.

Koomen ER, Joosse A, Herings RM, Casparie MK, Bergman W, Nijsten T, et al. Is statin use associated with a reduced incidence, a reduced Breslow thickness or delayed metastasis of melanoma of the skin? Eur J Cancer. 2007;43(17):2580–9.