Sildenafil Citrate (Viagra) induces therapeutic benefits for cancer patients by modulating nucleotide metabolism

Our immune system is essential to protect our body from cancer progression. Therefore, cancers that manipulate and evade our immune system have a better chance to continue surviving and proliferating. In the last decade, the discovery of key immune-regulatory checkpoints between immune effector cells and tumors has revolutionized oncologic treatments and patients’ outcome. Yet, despite the unprecedented durable response rates, most cancer patients either do not qualify to receive this treatment or do not benefit from it. Thus, there is a need to discover new biomarkers that can predict responders, and identify synergistic combination therapies that can improve the immune response against cancer.

Recently, we have shown that modulating tumor nucleotide metabolism by purine inhibitors can cause a cellular nucleotide imbalance favoring pyrimidines. This nucleotide imbalance generates a specific DNA signature termed Pyrimidine transversion mutation bias (PTMB), hence improving the immune response against cancer by affecting the immunogenicity of the antigens presented (6,7). Unfortunately, various agents that regulate nucleotide metabolism have immunosuppressive effects that interfere with the therapeutic effects of immunotherapy drugs. We now find that Viagra could generate PTMB in high PDE5A expressing cancers. Moreover, in low PDE5A expressing cancers, we show that Viagra reduces cancer migration in-vitro and restricts metastasis in-vivo. Furthermore, we demonstrate that Viagra promotes the immune response against non-responsive cancer PDX, and importantly, we further show that Viagra could be beneficial for various cancer patient’s survival. Our findings could potentially repurpose Viagra as a novel and promising adjuvant that synergized with various anti-cancer treatments.