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Treatment of Polarized Cystic Fibrosis Airway Cells With HGF Prevents VX-661-Rescued F508del-CFTR Destabilization Caused by Prolonged Co-exposure to VX-770

2021-12-22Journal article Open access
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dc.contributor.authorMatos, Ana M.
dc.contributor.authorJordan, Peter
dc.contributor.authorMatos, Paulo
dc.date.accessioned2022-02-03T16:49:34Z
dc.date.available2022-02-03T16:49:34Z
dc.date.issued2021-12-22
dc.description.abstractCystic fibrosis (CF), the most common inherited disease in Caucasians, is caused by mutations in CFTR, the most frequent of which is F508del. F508del causes ER retention and degradation of the mutant CFTR protein, but also defective channel gating and decreased half-life at the plasma membrane. Despite the recent successes with small molecule CFTR modulator drugs, the folding-corrector/gating-potentiator drug combinations approved for CF individuals carrying F508del-CFTR have sometimes produced severe side effects. Previously, we showed that a prolonged, 15-days treatment of polarized bronchial epithelial monolayers with the VX-809+VX-770 combination resulted in epithelial dedifferentiation effects that we found were caused specifically by VX-809. Moreover, prolonged VX-770 exposure also led to the destabilization of VX-809-rescued F508del-CFTR. Notably, co-treatment with the physiological factor HGF prevented VX-809-mediated epithelial differentiation and reverted the destabilizing effect of VX-770 on VX-809-rescued CFTR. Here, we show that prolonged treatment with VX-661, a second-generation corrector developed based on VX-809 structure, does not perturb epithelial integrity of polarized bronchial epithelial monolayers. Yet, its efficacy is still affected by co-exposure to VX-770, the potentiator present in all VX-661-containing combination therapies approved in the United States and Europe for treatment of F508del-CFTR carriers. Importantly, we found that co-treatment with HGF still ameliorated the impact of VX-770 in F508del-CFTR functional rescue by VX-661, without increasing cell proliferation (Ki-67) or altering the overall expression of epithelial markers (ZO-1, E-cadherin, CK8, CK18). Our findings highlight the importance of evaluating the cellular effects of prolonged exposure to CFTR modulators and suggest that the benefits of adding HGF to current combination therapies should be further investigated.pt_PT
dc.description.sponsorshipThis work was supported by the Grant PTDC/BIA-CEL/28408/2017 (to PJ and PM) and Center Grant UID/MULTI/04046/2019 to BioISI, both from the Portuguese Fundação para a Ciência e a Tecnologia.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationFront Mol Biosci. 2021 Dec 22;8:812101. doi: 10.3389/fmolb.2021.812101pt_PT
dc.identifier.doi10.3389/fmolb.2021.812101pt_PT
dc.identifier.issn2296-889X
dc.identifier.urihttp://hdl.handle.net/10400.18/7923
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherFrontierspt_PT
dc.relationBiosystems & Integrative Sciences Institute
dc.relation.publisherversionhttps://www.frontiersin.org/articles/10.3389/fmolb.2021.812101/fullpt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectCystic Fibrosispt_PT
dc.subjectHGFpt_PT
dc.subjectCell Signalingpt_PT
dc.subjectCell Differentiationpt_PT
dc.subjectVX-661pt_PT
dc.subjectVias de Transdução de Sinal e Patologias Associadaspt_PT
dc.titleTreatment of Polarized Cystic Fibrosis Airway Cells With HGF Prevents VX-661-Rescued F508del-CFTR Destabilization Caused by Prolonged Co-exposure to VX-770pt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleBiosystems & Integrative Sciences Institute
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FBIA-CEL%2F28408%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID%2FMulti%2F04046%2F2019/PT
oaire.citation.startPage812101pt_PT
oaire.citation.titleFrontiers in Molecular Biosciencespt_PT
oaire.citation.volume8pt_PT
oaire.fundingStream3599-PPCDT
oaire.fundingStream6817 - DCRRNI ID
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.embargofctAcesso de acordo com política editorial da revista.pt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isProjectOfPublication710163b5-23b3-4080-82a2-3b5d7a1ff579
relation.isProjectOfPublication35168786-8dfc-4a00-9759-dab3669fe1ae
relation.isProjectOfPublication.latestForDiscovery710163b5-23b3-4080-82a2-3b5d7a1ff579

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