Proteomic assessment of SKBR3/HER2+ breast cancer cellular response to Lapatinib and investigational Ipatasertib kinase inhibitors

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dc.contributor.authorKarcini, Arbaen
dc.contributor.authorMercier, Nicole R.en
dc.contributor.authorLazar, Iuliana M.en
dc.date.accessioned2025-02-05T13:19:57Zen
dc.date.available2025-02-05T13:19:57Zen
dc.date.issued2024-08-29en
dc.description.abstractIntroduction: Modern cancer treatment strategies aim at achieving cancer remission by using targeted and personalized therapies, as well as harnessing the power of the immune system to recognize and eradicate the cancer cells. To overcome a relatively short-lived response due to resistance to the administered drugs, combination therapies have been pursued. Objective: The objective of this study was to use high-throughput data generation technologies such as mass spectrometry and proteomics to investigate the broader implications, and to expand the outlook, of such therapeutic approaches. Specifically, we investigated the systems-level response of a breast cancer cell line model to a mixture of kinase inhibitors that has not been adopted yet as a standard therapeutic regime. Methods: Two critical pathways that sustain the growth and survival of cancer cells, EGFR and PI3K/AKT, were inhibited in SKBR3/HER2+ breast cancer cells with Lapatinib (Tyr kinase inhibitor) and Ipatasertib (Ser/Thr kinase inhibitor), and the landscape of the affected biological processes was investigated with proteomic technologies. Results: Over 800 proteins matched by three unique peptide sequences were affected by exposing the cells to the drugs. The work corroborated the anti-proliferative activity of Lapatinib and Ipatasertib and uncovered a range of impacted cancer-supportive hallmark processes, among which immune response, adhesion, and migration emerged as particularly relevant to the ability of drugs to effectively suppress the proliferation and dissemination of cancer cells. Changes in the expression of key cancer drivers such as oncogenes, tumor suppressors, EMT and angiogenesis regulators underscored the inhibitory effectiveness of drugs on cancer proliferation. The supplementation of Lapatinib with Ipatasertib further affected additional transcription factors and proteins involved in gene expression, trafficking, DNA repair, and development of multidrug resistance. Furthermore, over fifty of the impacted proteins represent approved or investigational targets in the DrugBank database, which through their protein-protein interaction networks can inform the selection of effective therapeutic partners. Conclusion: Altogether, the exposure of SKBR3/HER2+ cells to Lapatinib and Ipatasertib kinase inhibitors uncovered a broad plethora of yet untapped opportunities that can be further explored for enhancing the anti-cancer effects of each drug as well as of many other multi-drug therapies that target the EGFR/ERBB2 and PI3K/AKT pathways.en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.3389/fphar.2024.1413818en
dc.identifier.eissn1663-9812en
dc.identifier.issn1663-9812en
dc.identifier.orcidLazar, Maria [0000-0001-7746-7889]en
dc.identifier.otherPMC11391243en
dc.identifier.other1413818 (PII)en
dc.identifier.pmid39268460en
dc.identifier.urihttps://hdl.handle.net/10919/124497en
dc.identifier.volume15en
dc.language.isoenen
dc.publisherFrontiersen
dc.relation.urihttps://www.ncbi.nlm.nih.gov/pubmed/39268460en
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectHER2+ breast canceren
dc.subjectSKBR3en
dc.subjectdrug treatmenten
dc.subjectipatasertiben
dc.subjectlapatiniben
dc.subjectproteomeen
dc.titleProteomic assessment of SKBR3/HER2+ breast cancer cellular response to Lapatinib and investigational Ipatasertib kinase inhibitorsen
dc.title.serialFrontiers in Pharmacologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherJournal Articleen
dcterms.dateAccepted2024-08-09en
pubs.organisational-groupVirginia Techen
pubs.organisational-groupVirginia Tech/Scienceen
pubs.organisational-groupVirginia Tech/Science/Biological Sciencesen
pubs.organisational-groupVirginia Tech/Faculty of Health Sciencesen
pubs.organisational-groupVirginia Tech/All T&R Facultyen
pubs.organisational-groupVirginia Tech/Science/COS T&R Facultyen
pubs.organisational-groupVirginia Tech/VT Carilion School of Medicineen
pubs.organisational-groupVirginia Tech/VT Carilion School of Medicine/Surgeryen
pubs.organisational-groupVirginia Tech/VT Carilion School of Medicine/Psychiatry and Behavioral Medicineen
pubs.organisational-groupVirginia Tech/VT Carilion School of Medicine/Psychiatry and Behavioral Medicine/Secondary Appointment-Psychiatry and Behavioral Medicineen
pubs.organisational-groupVirginia Tech/VT Carilion School of Medicine/Surgery/Secondary Appointment-Surgeryen

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