1370 MTORC1 activity is increased in the skin of acne patients and is suppressed with isotretinoin treatment

Isotretinoin is the gold standard treatment for severe acne, but side effects, teratogenic risk, and complexities surrounding prescribing underscore need to identify new acne therapies. A hindrance advancing therapy an incomplete understanding of mechanism isotretinoin in skin. To this end, we performed RNA-seq on skin biopsies collected from upper backs 2 patient cohorts. We first compared transcriptomes lesional (L) & non-lesional (NL) (n = 55) healthy controls 20). Gene set enrichment analysis (GSEA) showed that mTORC1 signaling was positively enriched (NL: normalized score (NES) 2.92, p 5e-23; L: NES 2.9, 3.26e-24). In second cohort, NL patients (n=18) before after 1 week, 8 weeks 20 therapy. GSEA negatively at all timepoints baseline (1 week: -1.32, 4.36e-2; weeks: -2.91, 4.06e-29; -2.96, 5.62e-30). confirmed activity decreased by immunofluorescence staining tissue sections phospho-S6 ribosomal protein (p-S6), a downstream marker activity. At baseline, localized sebaceous glands granular layer epidermis. After one week treatment, observed 20% decrease p-S6 intensity within 5, 0.06). also used our data cohort query LINCS L1000 perturbagen database drug compounds have similar gene expression signatures isotretinoin. found mTOR PI3K/mTOR inhibitors were among top hits analysis. sum, findings demonstrate inhibits signaling. Taken together, results suggest could be therapeutic benefit patients.