PDE5 inhibitors and cancer, the direction has changed twice in 15 years

From suspicion of melanoma risk to the possibility of metastasis inhibition

Suggests risk Suggests benefit Neutral/Dismissed
2011BRAF lowers PDE5A

Cancer Cell. Report that BRAF mutation in melanoma reduces PDE5A expression, and low PDE5A increases invasiveness.

2014Sildenafil and melanoma occurrence association

JAMA Internal Medicine. Report on the association between sildenafil use and increased risk of melanoma in a US male cohort.

2016Listed on FDA safety surveillance list

In the same year, Cell Reports published experimental results that sildenafil promotes melanoma growth via the cGMP pathway.

2017Meta-analysis, causality dismissed

JNCI. There is an association, but no dose-response relationship. Risk of unrelated basal cell carcinoma also increased — interpreted as detection bias.

2026Identification of metastasis inhibition mechanism

Cancer Research. cGMP blocks NPC1, trapping cholesterol. Reduced lung metastasis in 3 mouse models, effect increased when combined with statins.

Remaining contradictions.The 2016 study stated that increased cGMP promotes melanoma growth, while the 2026 study states that the same increase in cGMP inhibits metastasis. The effect of the signaling molecule seems to differ depending on the cancer type and genetic background, but there is no settled explanation yet.