{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T09:24:15Z","timestamp":1768814655068,"version":"3.49.0"},"reference-count":77,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2023,8,4]],"date-time":"2023-08-04T00:00:00Z","timestamp":1691107200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Portuguese Foundation for Science and Technology (FCT), Portugal","award":["PTDC\/MED-ONC\/29402\/2017"],"award-info":[{"award-number":["PTDC\/MED-ONC\/29402\/2017"]}]},{"name":"Portuguese Foundation for Science and Technology (FCT), Portugal","award":["UIDB\/04138\/2020"],"award-info":[{"award-number":["UIDB\/04138\/2020"]}]},{"name":"Portuguese Foundation for Science and Technology (FCT), Portugal","award":["UIDP\/04138\/2020"],"award-info":[{"award-number":["UIDP\/04138\/2020"]}]},{"name":"Portuguese Foundation for Science and Technology (FCT), Portugal","award":["2020.07115.BD"],"award-info":[{"award-number":["2020.07115.BD"]}]},{"name":"FCT","award":["PTDC\/MED-ONC\/29402\/2017"],"award-info":[{"award-number":["PTDC\/MED-ONC\/29402\/2017"]}]},{"name":"FCT","award":["UIDB\/04138\/2020"],"award-info":[{"award-number":["UIDB\/04138\/2020"]}]},{"name":"FCT","award":["UIDP\/04138\/2020"],"award-info":[{"award-number":["UIDP\/04138\/2020"]}]},{"name":"FCT","award":["2020.07115.BD"],"award-info":[{"award-number":["2020.07115.BD"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Triple-negative breast cancer (TNBC) is a devastating BC subtype. Its aggressiveness, allied to the lack of well-defined molecular targets, usually culminates in the appearance of metastases that account for poor prognosis, particularly when they develop in the brain. Nevertheless, TNBC has been associated with epidermal growth factor receptor (EGFR) overexpression, leading to downstream phosphoinositide 3-kinase (PI3K) signaling activation. We aimed to unravel novel drug candidates for TNBC treatment based on EGFR and\/or PI3K inhibition. Using a highly metastatic TNBC cell line with brain tropism (MDA-MB-231 Br4) and a library of 27 drug candidates in silico predicted to inhibit EGFR, PI3K, or EGFR plus PI3K, and to cross the blood\u2013brain barrier, we evaluated the effects on cell viability. The half maximal inhibitory concentration (IC50) of the most cytotoxic ones was established, and cell cycle and death, as well as migration and EGFR pathway intervenient, were further evaluated. Two dual inhibitors emerged as the most promising drugs, with the ability to modulate cell cycle, death, migration and proliferation, morphology, and PI3K\/AKT cascade players such as myocyte enhancer factor 2C (MEF2C) and forkhead box P1 (FOXP1). This work revealed EGFR\/PI3K dual inhibitors as strong candidates to tackle brain metastatic TNBC cells.<\/jats:p>","DOI":"10.3390\/cancers15153973","type":"journal-article","created":{"date-parts":[[2023,8,4]],"date-time":"2023-08-04T09:28:29Z","timestamp":1691141309000},"page":"3973","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Abrogating Metastatic Properties of Triple-Negative Breast Cancer Cells by EGFR and PI3K Dual Inhibitors"],"prefix":"10.3390","volume":"15","author":[{"given":"Ana Rita","family":"Garcia","sequence":"first","affiliation":[{"name":"Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal"},{"name":"Department of Pharmaceutical Sciences and Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal"}]},{"given":"Avilson","family":"Mendes","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal"},{"name":"Department of Pharmaceutical Sciences and Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7089-7675","authenticated-orcid":false,"given":"Carlos","family":"Cust\u00f3dia","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisbon, Portugal"}]},{"given":"Cl\u00e1udia C.","family":"Faria","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisbon, Portugal"},{"name":"Department of Neurosurgery, Hospital de Santa Maria, Centro Hospitalar Universit\u00e1rio Lisboa Norte (CHULN), Av. Prof. Egas Moniz, 1649-035 Lisbon, Portugal"}]},{"given":"Jo\u00e3o T.","family":"Barata","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisbon, Portugal"}]},{"given":"Rui","family":"Malh\u00f3","sequence":"additional","affiliation":[{"name":"BioISI\u2014Biosystems and Integrative Sciences Institute, Faculty of Sciences, Universidade de Lisboa, Campo Grande, 1746-016 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4639-6883","authenticated-orcid":false,"given":"In\u00eas","family":"Figueira","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal"},{"name":"Farm-ID\u2014Faculty of Pharmacy Association for Research and Development, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8493-4649","authenticated-orcid":false,"given":"Maria Alexandra","family":"Brito","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal"},{"name":"Department of Pharmaceutical Sciences and Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1007\/s12013-014-0459-6","article-title":"Breast Cancer: Epidemiology and Etiology","volume":"72","author":"Tao","year":"2015","journal-title":"Cell Biochem. 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