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. 2021 Sep 10;12:5386. doi: 10.1038/s41467-021-25700-6

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© The Author(s) 2021

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 7 — a Expression of a cohort of genes driving acquisition of CDK4/6i resistance was significantly suppressed in the context of combination treatment (n = 3). The P values were calculated by Student’s t-test (two-sided). **P < 0.01. b Immunoblot showing the RB1 and CDK6 protein levels in normal parental and CDK4/6i-resistant daughter breast cancer cells. c Immunoblot showing that addition of D 4476 potentiated the suppressing efficacy of ribociclib in CDK4/6i resistant cells. d RT-qPCR analysis showing that combination of D 4476 overcomes the CDK4/6i resistance in suppressing cell cycle gene transcription in CDK4/6i-resistant MCF7 cells (n = 3). The P values were calculated by Student’s t-test (two-sided). **P < 0.01. Cells were treated with ribociclib (1 μM), D 4476 (50 μM), and ribociclib-D 4476 combination, respectively, for 24 h. e Combination of D 4476 potentiated the efficacy of ribociclib in suppressing colony formation in MCF7 and T-47D resistant breast cancer cells. f Pharmacokinetic curve of CK1ε inhibitor D 4476 in vivo. A single dose of D 4476 was administrated in ICR mice and blood concentration of D 4476 at indicated time points was measured. g 4T1 xenograft assay showing that combination of D 4476 with ribociclib led to decreased tumor weight. The P values were calculated by Student’s t-test (two-sided). *P < 0.05, **P < 0.01. h Combination of D 4476 with ribociclib retarded MDA-MB-231 tumor growth in vivo. Statistical differences were assessed by two-way ANOVA (two-sided). *P < 0.05, **: P < 0.01. i Immunoblot analysis of MDA-MB-231 tumors treated with vehicle, ribociclib, D 4476, and Combo (ribociclib-D 4476), respectively. j Combination of D 4476 with ribociclib resulted in significant improvement of overall survival in triple negative breast cancer PDX model. The P value was calculated by log-rank test. **P < 0.01. k Combination of ribociclib, D 4476 and Trastuzumab retarded BT-474 tumor growth. Data are presented as mean values ± SEM. The relevant raw data and uncropped blots are provided in Source Data.