PRIMA-1MET/APR-246 Can Partially Rescue In Vitro Cell Adhesion of Patient-Derived Junctional Epidermolysis Bullosa Epidermal Cells

The epithelial transcription factor TP63 is critical for basal epithelial cell adhesion and wound healing ( Pecorari et al., 2022 Pecorari R. Bernassola F. Melino G. Candi E. Distinct interactors define the p63 transcriptional signature in epithelial development or cancer. Biochem J. 2022; 479: 1375-1392 Crossref PubMed Scopus (7) Google Scholar ). TP63 (the gene encoding p63) regulates ITGB4, one of the major integrin receptors for laminin-332 (LM332). Moreover, TP63 is also known to regulate ZNF750 ( Sen et al., 2012 Sen G.L. Boxer L.D. Webster D.E. Bussat R.T. Qu K. Zarnegar B.J. et al. ZNF750 is a p63 target gene that induces KLF4 to drive terminal epidermal differentiation. Dev Cell. 2012; 22: 669-677 Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar ), which in turn controls LM332 gene expression (LAMA3, LAMB3, LAMC2) ( Soares et al., 2019 Soares E. Xu Q. Li Q. Qu J. Zheng Y. Raeven H.H.M. et al. Single-cell RNA-seq identifies a reversible mesodermal activation in abnormally specified epithelia of p63 EEC syndrome. Proc Natl Acad Sci USA. 2019; 116: 17361-17370 Crossref PubMed Scopus (17) Google Scholar ). p63 function is dysregulated in several acquired and congenital skin diseases; notably, pathogenic variants in TP63 are responsible for several ectodermal dysplasia subtypes ( Peschel et al., 2022 Peschel N. Wright J.T. Koster M.I. Clarke A.J. Tadini G. Fete M. et al. Molecular pathway-based classification of ectodermal dysplasias: first five-yearly update. Genes. 2022; 13: 2327 Crossref PubMed Scopus (10) Google Scholar ), including ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (MIM106260), which is characterized by severe skin erosions at birth. Recently, we demonstrated that PRIMA-1MET/APR-246, a small compound able to reactivate mutated p53 in human cancers, could be repurposed to improve epidermal commitment of ankyloblepharon-ectodermal defects-cleft lip/palate–derived pluripotent stem cells ( Shalom-Feuerstein et al., 2013 Shalom-Feuerstein R. Serror L. Aberdam E. Müller F.J. van Bokhoven H. Wiman K.G. et al. Impaired epithelial differentiation of induced pluripotent stem cells from ectodermal dysplasia-related patients is rescued by the small compound APR-246/PRIMA-1MET. Proc Natl Acad Sci USA. 2013; 110: 2152-2156 Crossref PubMed Scopus (58) Google Scholar ) and treat skin erosions in patients with ankyloblepharon-ectodermal defects-cleft lip/palate ( Aberdam et al., 2020 Aberdam E. Roux L.N. Secrétan P.H. Boralevi F. Schlatter J. Morice-Picard F. et al. Improvement of epidermal covering on AEC patients with severe skin erosions by PRIMA-1MET/APR-246. Cell Death Dis. 2020; 11: 30 Crossref PubMed Scopus (11) Google Scholar ). Such treatment led to increased expression of genes involved in cell adhesion and epidermal differentiation, thereby indicating that PRIMA-1MET might have potential as a broader therapeutic tool for genodermatoses in which p63 is directly or indirectly modulating either cell adhesion or differentiation.