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Circulating tumor DNA analyses reveal novel resistance mechanisms to CDK inhibition in metastatic breast cancer

Abbosh, C; Swanton, C; Birkbak, NJ; (2018) Circulating tumor DNA analyses reveal novel resistance mechanisms to CDK inhibition in metastatic breast cancer. Annals of Oncology 10.1093/annonc/mdy017. (In press). Green open access

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Abstract

Cyclin-dependent kinase (CDK) 4/6 inhibition has been demonstrated to improve progression-free survival (PFS) in patients with human epidermal growth factor receptor 2 (HER2−), hormone receptor positive (HR+) in advanced breast cancer [1–3]. Palbociclib, ribociclib and abemaciclib are orally bioavailable selective CDK 4/6 inhibitors. These small molecules likely bind the ATP-binding pocket within the CDK4/6 protein kinases thereby inhibiting phosphorylation of retinoblastoma tumour suppressor protein (Rb). In its hypophosphorylated state Rb remains bound to E2F thereby preventing progression through the G1-S-cell cycle checkpoint [4]. The mechanism behind the observed efficacy of CDK inhibition in metastatic breast cancer may relate to a dependence of HR+ breast cancer on CDK4/6 activity to override Rb mediated repression of cell cycle progression (Figure 1) [5].

Type: Article
Title: Circulating tumor DNA analyses reveal novel resistance mechanisms to CDK inhibition in metastatic breast cancer
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/annonc/mdy017
Publisher version: http://doi.org/10.1093/annonc/mdy017
Language: English
Additional information: Copyright © The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/10044560
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