Therapeutic response to CDK4/6 inhibition in breast cancer defined by ex vivo analyses of human tumors

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dc.contributor.authorDean, J.
dc.contributor.authorMcClendon, A.
dc.contributor.authorHickey, T.
dc.contributor.authorButler, L.
dc.contributor.authorTilley, W.
dc.contributor.authorWitkiewicz, A.
dc.contributor.authorKnudsen, E.
dc.date.issued2012
dc.description.abstractTo model the heterogeneity of breast cancer as observed in the clinic, we employed an ex vivo model of breast tumor tissue. This methodology maintained the histological integrity of the tumor tissue in unselected breast cancers, and importantly, the explants retained key molecular markers that are currently used to guide breast cancer treatment (e.g., ER and Her2 status). The primary tumors displayed the expected wide range of positivity for the proliferation marker Ki67, and a strong positive correlation between the Ki67 indices of the primary and corresponding explanted tumor tissues was observed. Collectively, these findings indicate that multiple facets of tumor pathophysiology are recapitulated in this ex vivo model. To interrogate the potential of this preclinical model to inform determinants of therapeutic response, we investigated the cytostatic response to the CDK4/6 inhibitor, PD-0332991. This inhibitor was highly effective at suppressing proliferation in approximately 85% of cases, irrespective of ER or HER2 status. However, 15% of cases were completely resistant to PD-0332991. Marker analyses in both the primary tumor tissue and the corresponding explant revealed that cases resistant to CDK4/6 inhibition lacked the RB-tumor suppressor. These studies provide important insights into the spectrum of breast tumors that could be treated with CDK4/6 inhibitors, and defines functional determinants of response analogous to those identified through neoadjuvant studies.
dc.description.statementofresponsibilityJeffry L. Dean, A. Kathleen McClendon, Theresa E. Hickey, Lisa M. Butler, Wayne D. Tilley, Agnieszka K. Witkiewicz and Erik S. Knudsen
dc.identifier.citationCell Cycle, 2012; 11(14):2756-2761
dc.identifier.doi10.4161/cc.21195
dc.identifier.issn1538-4101
dc.identifier.issn1551-4005
dc.identifier.orcidHickey, T. [0000-0002-2752-730X]
dc.identifier.orcidButler, L. [0000-0003-2698-3220]
dc.identifier.orcidTilley, W. [0000-0003-1893-2626]
dc.identifier.urihttp://hdl.handle.net/2440/73767
dc.language.isoen
dc.publisherLandes Bioscience
dc.rights© 2012 Landes Bioscience
dc.source.urihttps://doi.org/10.4161/cc.21195
dc.subjectCell cycle
dc.subjectPD0332991
dc.subjectbreast cancer
dc.subjectER
dc.subjectex vivo
dc.titleTherapeutic response to CDK4/6 inhibition in breast cancer defined by ex vivo analyses of human tumors
dc.typeJournal article
pubs.publication-statusPublished

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