Epigenetic reprogramming of cell cycle genes by ACK1 promotes breast cancer resistance to CDK4/6 inhibitor

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dc.contributor.authorSawant, Mithila
dc.contributor.authorWilson, Audrey
dc.contributor.authorSridaran, Dhivya
dc.contributor.authorMahajan, Kiran
dc.contributor.authorO'Conor, Christopher J.
dc.contributor.authorHagemann, Ian S.
dc.contributor.authorLuo, Jingqin
dc.contributor.authorWeimholt, Cody
dc.contributor.authorLi, Tiandao
dc.contributor.authorRoa, Juan Carlos
dc.contributor.authorPandey, Akhilesh
dc.contributor.authorWu, Xinyan
dc.contributor.authorMahajan, Nupam P.
dc.date.accessioned2025-01-20T20:10:27Z
dc.date.available2025-01-20T20:10:27Z
dc.date.issued2023
dc.description.abstractHormone receptor-positive, HER2-negative advanced breast cancers exhibit high sensitivity to CDK4/6 inhibitors such as palbociclib. However, most patients inevitably develop resistance, thus identification of new actionable therapeutic targets to overcome the recurrent disease is an urgent need. Immunohistochemical studies of tissue microarray revealed increased activation of non-receptor tyrosine kinase, ACK1 (also known as TNK2) in most of the breast cancer subtypes, independent of their hormone receptor status. Chromatin immunoprecipitation studies demonstrated that the nuclear target of activated ACK1, pY88-H4 epigenetic marks, were deposited at cell cycle genes, CCNB1, CCNB2 and CDC20, which in turn initiated their efficient transcription. Pharmacological inhibition of ACK1 using its inhibitor, (R)-9b dampened CCNB1, CCNB2 and CDC20 expression, caused G2/M arrest, culminating in regression of palbociclib-resistant breast tumor growth. Further, (R)-9b suppressed expression of CXCR4 receptor, which resulted in significant impairment of metastasis of breast cancer cells to lung. Overall, our pre-clinical data identifies activated ACK1 as an oncogene that epigenetically controls the cell cycle genes governing the G2/M transition in breast cancer cells. ACK1 inhibitor, (R)-9b could be a novel therapeutic option for the breast cancer patients that have developed resistance to CDK4/6 inhibitors.
dc.fuente.origenWOS
dc.identifier.doi10.1038/s41388-023-02747-x
dc.identifier.eissn1476-5594
dc.identifier.issn0950-9232
dc.identifier.urihttps://doi.org/10.1038/s41388-023-02747-x
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/92070
dc.identifier.wosidWOS:001009380600001
dc.issue.numero29
dc.language.isoen
dc.pagina.final2277
dc.pagina.inicio2263
dc.revistaOncogene
dc.rightsacceso restringido
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleEpigenetic reprogramming of cell cycle genes by ACK1 promotes breast cancer resistance to CDK4/6 inhibitor
dc.typeartículo
dc.volumen42
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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