Sequential activation of E2F via Rb degradation and c-Myc drives resistance to CDK4/6 inhibitors in breast cancer Journal Article

   

Authors:	Kim, S.; Armand, J.; Safonov, A.; Zhang, M.; Soni, R. K.; Schwartz, G.; McGuinness, J. E.; Hibshoosh, H.; Razavi, P.; Kim, M.; Chandarlapaty, S.; Yang, H. W.
Article Title:	Sequential activation of E2F via Rb degradation and c-Myc drives resistance to CDK4/6 inhibitors in breast cancer
Abstract:	Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) are key therapeutic agents in the management of metastatic hormone-receptor-positive breast cancer. However, the emergence of drug resistance limits their long-term efficacy. Here, we show that breast cancer cells develop CDK4/6i resistance via a sequential two-step process of E2F activation. This process entails retinoblastoma (Rb)-protein degradation, followed by c-Myc-mediated amplification of E2F transcriptional activity. CDK4/6i treatment halts cell proliferation in an Rb-dependent manner but dramatically reduces Rb-protein levels. However, this reduction in Rb levels insufficiently induces E2F activity. To develop CDK4/6i resistance, upregulation or activating mutations in mitogenic or hormone signaling are required to stabilize c-Myc levels, thereby augmenting E2F activity. Our analysis of pre-treatment tumor samples reveals a strong correlation between c-Myc levels, rather than Rb levels, and poor therapeutic outcomes after CDK4/6i treatment. Moreover, we propose that proteasome inhibitors can potentially reverse CDK4/6i resistance by restoring Rb levels. © 2023 The Author(s)
Keywords:	breast cancer; drug resistance; retinoblastoma protein; e2f transcription factors; cdk4/6 inhibitors; cp: cancer
Journal Title:	Cell Reports
Volume:	42
Issue:	11
ISSN:	2211-1247
Publisher:	Cell Press
Date Published:	2023-11-28
Start Page:	113198
Language:	English
DOI:	10.1016/j.celrep.2023.113198
PROVIDER:	scopus
PUBMED:	37865915
PMCID:	PMC10757862
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85174458279&doi=10.1016%2fj.celrep.2023.113198&partnerID=40&md5=eda1d182a8519c02958bd2655977891d
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/210491