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

Fig. 5. Suppression of CK1ε prevents CDK4/6i-induced CDK6 upregulation.

Fig. 5

a Immunoblot showing that CDK4-deficiency resulted in CDK6 accumulation, which can be efficiently blocked by CK1ε kinase inhibitor D 4476. b Immunoblot showing that silencing of CK1ε abolished ribociclib-induced CDK6 accumulation. c Knocking-down of CK1ε accelerated SP1 degradation. Statistical differences were assessed by two-way ANOVA. **P < 0.01. d Nuclear accumulation of SP1 was significantly reduced by knocking-down of CK1ε. e Knocking-down of CK1ε diminished accumulation of SP1 on CDK6 promoter region (n = 3). The P value was calculated by Student’s t-test (two-sided). **P < 0.01. f Treatment of MDA-MB-231 cells with D 4476 blocked CDK6 accumulation and potentiated the efficacy of ribociclib on inhibiting RB1 phosphorylation. g CDK6-deficiency potentiated the suppressing efficacy of ribociclib on RB1 phosphorylation in MDA-MB-231 cells. h Knocking-down of CK1ε sensitized MCF7 and MDA-MB-231 cells to ribociclib treatment. i Combination of D 4476 and ribociclib blocked CDK6 accumulation and enhanced the suppressive effect of ribociclib on cell cycle gene expression in MDA-MB-231 cells. Scale bar: 10 uM. j A schematic diagram showing the molecular mechanisms by which D 4476 synergizes with ribociclib to prevent acquired CDK4/6i resistance. Data are presented as mean values ± SEM. The relevant raw data and uncropped blots are provided in Source Data.