1033 The potential pro-proliferative role of polo-like kinase 4 in non-melanoma skin cancer

Abstract

Isotretinoin is the gold standard treatment for moderate to severe acne but its use is limited by its side effect profile. We need to accelerate drug discovery for moderate to severe acne. Drug-repurposing is one approach to accelerating drug discovery and those drugs that elicit a similar "signature" to isotretinoin may be beneficial as acne therapies. In order to generate "isotretinoin's signature", a complete understanding of the mechanisms by which isotretinoin improves acne in human patients is required. Using a multi-omics approach, we performed a comprehensive study to investigate the effects of isotretinoin in whole skin, whole blood and the facial skin microbiome in 18 acne patients before, during and after isotretinoin therapy. Acne severity and lesion counts, sebum measurements and clinical response were documented at each study visit. RNA-Sequencing was performed cell lines and whole skin and blood samples from patients. The serum chemokine and cytokine profiles were determined by multiplex ELISA assays. The follicular skin microbiome was sampled by cyanoacrylate follicular biopsy and subjected to whole genome shot-gun sequencing. Parallel in vitro experiments using human SEB-1 sebocytes, keratinocytes and fibroblasts exposed to isotretinoin were done to determine the skin cell-specific effects of isotretinoin. Our data sets allow for the development of a network model of isotretinoin effects that can be used to test existing drugs and novel compounds for desired effects in acne treatment.