Oxygen tension-dependent variability in the cancer cell kinome impacts signaling pathways and response to targeted therapies

dc.contributor.authorAdebayo, Adedeji K.
dc.contributor.authorBhat-Nakshatri, Poornima
dc.contributor.authorDavis, Christopher
dc.contributor.authorAngus, Steven P.
dc.contributor.authorErdogan, Cihat
dc.contributor.authorGao, Hongyu
dc.contributor.authorGreen, Nick
dc.contributor.authorKumar, Brijesh
dc.contributor.authorLiu, Yunlong
dc.contributor.authorNakshatri, Harikrishna
dc.contributor.departmentSurgery, School of Medicine
dc.date.accessioned2024-08-26T07:47:18Z
dc.date.available2024-08-26T07:47:18Z
dc.date.issued2024-05-21
dc.description.abstractMost cells in solid tumors are exposed to oxygen levels between 0.5% and 5%. We developed an approach that allows collection, processing, and evaluation of cancer and non-cancer cells under physioxia, while preventing exposure to ambient air. This aided comparison of baseline and drug-induced changes in signaling pathways under physioxia and ambient oxygen. Using tumor cells from transgenic models of breast cancer and cells from breast tissues of clinically breast cancer-free women, we demonstrate oxygen-dependent differences in cell preference for epidermal growth factor receptor (EGFR) or platelet-derived growth factor receptor beta (PDGFRβ) signaling. Physioxia caused PDGFRβ-mediated activation of AKT and extracellular regulated kinase (ERK) that reduced sensitivity to EGFR and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) inhibition and maintained PDGFRβ+ epithelial-mesenchymal hybrid cells with potential cancer stem cell (CSC) properties. Cells in ambient air displayed differential EGFR activation and were more sensitive to targeted therapies. Our data emphasize the importance of oxygen considerations in preclinical cancer research to identify effective drug targets and develop combination therapy regimens.
dc.eprint.versionFinal published version
dc.identifier.citationAdebayo AK, Bhat-Nakshatri P, Davis C, et al. Oxygen tension-dependent variability in the cancer cell kinome impacts signaling pathways and response to targeted therapies. iScience. 2024;27(6):110068. Published 2024 May 21. doi:10.1016/j.isci.2024.110068
dc.identifier.urihttps://hdl.handle.net/1805/42923
dc.language.isoen_US
dc.publisherElsevier
dc.relation.isversionof10.1016/j.isci.2024.110068
dc.relation.journaliScience
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.sourcePMC
dc.subjectBiochemistry
dc.subjectCell
dc.subjectCancer
dc.subjectProteomics
dc.subjectTranscriptomics
dc.titleOxygen tension-dependent variability in the cancer cell kinome impacts signaling pathways and response to targeted therapies
dc.typeArticle
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