Abstract P3-06-01: Mechanisms of resistance to CDK4/6 inhibition in ER+ breast cancer

Autor: Peter Olson, Koleen Eisele, Zhou Zhu, Valeria Fantin, Danan Li, David J. Shields, John Chionis, Todd VanArsdale, Chaoting Liu, Jing Yuan, Nathan V. Lee, Kim Arndt
Rok vydání: 2016
Předmět:
Zdroj: Cancer Research. 76:P3-06
ISSN: 1538-7445
0008-5472
DOI: 10.1158/1538-7445.sabcs15-p3-06-01
Popis: Estrogen receptor positive breast cancers show frequent deregulation of Cyclin D-CDK4/6 signaling. Combining CDK4/6 inhibitors with hormonal therapies produces clinical benefit, supporting drug approval of the first CDK4/6 inhibitor, Palbociclib, in combination with Letrozole or Fulvestrant. Due to the adaptive nature of cancers, development of drug resistance is common and resistance to CDK4/6 inhibitors can be expected. To understand potential mechanisms of resistance to palbociclib, ER+ breast cancer cells were made resistant to Palbociclib in vitro. Characterization of resistance models derived from T47D and MCF7 cell lines revealed different mechanisms of resistance to Palbociclib. Resistant T47D revealed loss of functional Rb through a large 3 prime genomic deletion of RB1. Palbociclib failed to inhibit proliferation of these cells confirming Rb inactivation as the primary mechanism of Palbociclib activity. Palbociclib-resistant MCF7 cells retained Rb mRNA and protein expression suggesting direct loss of Rb function was not the mechanism of resistance. RNAseq and CNV analysis of several resistant MCF7 lines revealed distinguishing features of the resistant lines including up-regulation of E2F, TGFβ, WNT and NF-κB transcriptional networks. Also, proteomic analysis showed that prominent features of all the resistant MCF7 cells included elevated Myc expression as well as increased abundance of Rb, phosphorylated Rb, E2F1 and its downstream targets Cyclin E1, Cyclin A2 among others. Palbociclib treatment of resistant MCF7 lines showed that CDK4/6 inhibition still modulated phosphorylated Rb and E2F1 levels, but repressed levels were higher than compared to basal levels of vehicle treated parental MCF7 cells. Given the precedence for Cyclin E/CDK2 activity to redundantly regulate Rb function at the G1 checkpoint, Cyclin E1 expression was inhibited using shRNA. Results show that knockdown of Cyclin E1 protein in Palbociclib-resistant cells restores sensitivity to Palbociclib. Palbociclib-resistant MCF7 transcriptomes also exhibited significantly decreased expression of Estrogen Receptor target genes. Resistant cells proved unresponsive to the ER antagonist Fulvestrant, suggesting a loss of dependence on ER signaling. Cyclin E1 dysregulation is also implicated in resistance to hormonal therapy and Cyclin E1 knockdown resensitized Palbociclib-resistant MCF7 cells to Fulvestrant treatment. The observations of cross resistance to CDK4/6 inhibitors and hormonal therapy highlight the co-dependence of Cyclin D-CDK4/6 and ER signaling in ER+ breast cancer. Continued studies are focused on describing the alterations driving increased Cyclin E1 expression in response to CDK4/6 inhibition and strategies to circumvent development of resistance via Cyclin E/CDK2 signaling. Citation Format: Lee NV, Eisele KJ, Chionis J, Yuan J, Zhu Z, Liu C, Li D, Olson PA, Fantin V, Arndt KT, Shields DJ, VanArsdale TL. Mechanisms of resistance to CDK4/6 inhibition in ER+ breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-06-01.
Databáze: OpenAIRE
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