IB-DNQ and Rucaparib dual treatment alters cell cycle regulation and DNA repair in triple negative breast cancer cells

dc.contributor.authorRunnebohm, Avery M.
dc.contributor.authorWijeratne, H. R. Sagara
dc.contributor.authorPeck Justice, Sarah A.
dc.contributor.authorWijeratne, Aruna B.
dc.contributor.authorRoy, Gitanjali
dc.contributor.authorSingh, Naveen
dc.contributor.authorHergenrother, Paul
dc.contributor.authorBoothman, David A.
dc.contributor.authorMotea, Edward A.
dc.contributor.authorMosley, Amber L.
dc.contributor.departmentBiochemistry and Molecular Biology, School of Medicine
dc.date.accessioned2024-08-02T10:56:31Z
dc.date.available2024-08-02T10:56:31Z
dc.date.issued2024-05-18
dc.description.abstractBackground: Triple negative breast cancer (TNBC), characterized by the lack of three canonical receptors, is unresponsive to commonly used hormonal therapies. One potential TNBC-specific therapeutic target is NQO1, as it is highly expressed in many TNBC patients and lowly expressed in non-cancer tissues. DNA damage induced by NQO1 bioactivatable drugs in combination with Rucaparib-mediated inhibition of PARP1-dependent DNA repair synergistically induces cell death. Methods: To gain a better understanding of the mechanisms behind this synergistic effect, we used global proteomics, phosphoproteomics, and thermal proteome profiling to analyze changes in protein abundance, phosphorylation and protein thermal stability. Results: Very few protein abundance changes resulted from single or dual agent treatment; however, protein phosphorylation and thermal stability were impacted. Histone H2AX was among several proteins identified to have increased phosphorylation when cells were treated with the combination of IB-DNQ and Rucaparib, validating that the drugs induced persistent DNA damage. Thermal proteome profiling revealed destabilization of H2AX following combination treatment, potentially a result of the increase in phosphorylation. Kinase substrate enrichment analysis predicted altered activity for kinases involved in DNA repair and cell cycle following dual agent treatment. Further biophysical analysis of these two processes revealed alterations in SWI/SNF complex association and tubulin / p53 interactions. Conclusions: Our findings that the drugs target DNA repair and cell cycle regulation, canonical cancer treatment targets, in a way that is dependent on increased expression of a protein selectively found to be upregulated in cancers without impacting protein abundance illustrate that multi-omics methodologies are important to gain a deeper understanding of the mechanisms behind treatment induced cancer cell death.
dc.eprint.versionPre-Print
dc.identifier.citationRunnebohm AM, Wijeratne HRS, Justice SAP, et al. IB-DNQ and Rucaparib dual treatment alters cell cycle regulation and DNA repair in triple negative breast cancer cells. Preprint. bioRxiv. 2024;2024.05.15.594427. Published 2024 May 18. doi:10.1101/2024.05.15.594427
dc.identifier.urihttps://hdl.handle.net/1805/42570
dc.language.isoen_US
dc.publisherbioRxiv
dc.relation.isversionof10.1101/2024.05.15.594427
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0
dc.sourcePMC
dc.subjectTriple negative breast cancer
dc.subjectIB-DNQ
dc.subjectRucaparib
dc.subjectMultiomics
dc.subjectMass spectrometry
dc.subjectDNA damage
dc.subjectCell cycle
dc.titleIB-DNQ and Rucaparib dual treatment alters cell cycle regulation and DNA repair in triple negative breast cancer cells
dc.typeArticle
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