545 Precision medicine in psoriasis: machine learning and proteomics join forces to develop a blood-based test to predict response to tofacitinib or Etanercept in psoriasis patients

Abstract

We previously showed that delphinidin, a dietary small molecule, possesses prodifferentiation and anti-proliferative properties with unknown mechanism, and recently observed deregulated PI3K/Akt/mTOR signaling in human psoriasis and imiquimod (IMQ)induced murine psoriasis-like skin lesions. Using KINOMEscan, a competitive kinase binding assay platform and subsequent K d determinations we observed that from a panel of 104 kinases screened delphinidin bound to several lipid (PIK3CG, PIK3C2B, and PIK3CA) and serine/threonine (PIM1, PIM3, mTOR, S6K1, PLK1, and PLK2) kinases (P< 0.05). We further corroborated these data using Surface Plasmon Resonance and in silico molecular modeling and observed kinetic (P<0.05) and high affinity direct interactions of delphinidin with PI3K (a, and g), mTOR and p70S6K with favorable free energy values and little affinity for Akt. Delphinidin treatment of interleukin 22 or TPA pre-stimulated human epidermal keratinocytes (NHEK), significantly (p<0.05) inhibited proliferation, expression of PI3Ks and phosphorylated Akt, mTOR and p70S6K, and secretion of pro-inflammatory cytokines. Further, we established the in vivo relevance of these findings using tissues derived from topically treated delphinidin (1mg/cm 2 skin) on IMQ-induced mouse psoriasis-like skin lesions. qPCR, western blot and multiplex ELISA analyses demonstrated significant (p<0.05) decrease in; i) PI3Ks, phosphorylated Akt, mTOR and p70S6K expression, ii) proliferation, epidermal thicknesses and skin inflammation, and iii) psoriasis-related inflammatory cytokines/chemokines (P<0.01) when compared with IMQ-treated skin. Taken together, our data demonstrate that delphinidin potently binds and inhibits key kinases including the PI3/Akt/mTOR signaling involved in psoriasis pathophysiology, and alleviates (IMQ)-induced murine psoriasis-like disease. We suggest further studies to develop delphinidin either alone or as an adjuvant to current therapies, as specific PI3K/AKT/mTOR kinase inhibitor for the treatment of psoriasis.