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Phe508del causes not only intracellular retention and premature degradation of the mutant CFTR protein, but also defective channel gating and decreased half-life when experimentally rescued to the plasma membrane (PM). Despite recent successes in the functional rescue of several CFTR mutations with small-molecule drugs, the folding-corrector\/gating-potentiator drug combinations approved for Phe508del-CFTR homozygous patients have shown only modest benefit. Several factors have been shown to contribute to this outcome, including an unexpected intensification of corrector-rescued Phe508del-CFTR PM instability after persistent co-treatment with potentiator drugs. We have previously shown that acute co-treatment with hepatocyte growth factor (HGF) can significantly enhance the chemical correction of Phe508del-CFTR. HGF coaxes the anchoring of rescued channels to the actin cytoskeleton via induction of RAC1 GTPase signalling. Here, we demonstrate that a prolonged, 15-day HGF treatment also significantly improves the functional rescue of Phe508del-CFTR by the VX-809 corrector\/VX-770 potentiator combination, in polarized bronchial epithelial monolayers. Importantly, we found that HGF treatment also prevented VX-770-mediated destabilization of rescued Phe508del-CFTR and enabled further potentiation of the rescued channels. Most strikingly, prolonged HGF treatment prevented previously unrecognized epithelial dedifferentiation effects of sustained exposure to VX-809. This was observed in epithelium-like monolayers from both lung and intestinal origin, representing the two systems most affected by adverse symptoms in patients treated with VX-809 or the VX-809\/VX-770 combination. Taken together, our findings strongly suggest that co-administration of HGF with corrector\/potentiator drugs could be beneficial for CF patients.<\/jats:p>","DOI":"10.1038\/s41598-018-31514-2","type":"journal-article","created":{"date-parts":[[2018,8,23]],"date-time":"2018-08-23T11:34:28Z","timestamp":1535024068000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Prolonged co-treatment with HGF sustains epithelial integrity and improves pharmacological rescue of Phe508del-CFTR"],"prefix":"10.1038","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0160-256X","authenticated-orcid":false,"given":"Ana M.","family":"Matos","sequence":"first","affiliation":[]},{"given":"Andreia","family":"Gomes-Duarte","sequence":"additional","affiliation":[]},{"given":"M\u00e1rcia","family":"Faria","sequence":"additional","affiliation":[]},{"given":"Patr\u00edcia","family":"Barros","sequence":"additional","affiliation":[]},{"given":"Peter","family":"Jordan","sequence":"additional","affiliation":[]},{"given":"Margarida D.","family":"Amaral","sequence":"additional","affiliation":[]},{"given":"Paulo","family":"Matos","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2018,8,29]]},"reference":[{"key":"31514_CR1","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1146\/annurev.biochem.75.103004.142532","volume":"77","author":"JR Riordan","year":"2008","unstructured":"Riordan, J. 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