Fig. 1: High MYC expression drives resistance to CDK4/6i by masking pRB1.

a Pharmacological tests of palbociclib using mini-PDX models^72,73, palbociclib sensitivity results for control and MYC amplified tumors. Data were shown as the mean ± SD of six mice (n = 6). Two-tailed unpaired Student’s t-test. P values based on the order of appearance: 0.0034 and 0.7280. Volcano plots showing differentially regulated genes by RNA-seq analysis from CDK4/6i treated T24 (b) and UMUC14 (c) cells. d Control or MYC-knockdown T24 cells were harvested for RNA-seq analysis and pathway analysis. Differentially regulated genes with more than 2-fold change were included in this pathway analysis. Color represents the level of significance, and P value adjusted. Data is analyzed by standard accumulative hypergeometric statistical test. e Heatmap showing the differential expression of the indicated pathway genes downregulated after MYC knockdown in T24 cells. f Control or MYC-overexpressing T24, C4-2, and MDA-MB-231 cells were harvested for western blotting with the indicated antibodies. g Quantification of colony formation of control or MYC-overexpressing T24, C4-2, and MDA-MB-231 cells treated with vehicle or palbociclib. Data were shown as the mean ± SD of three independent experiments (n = 3). Two-tailed unpaired Student’s t-test. P values based on the order of appearance: 0.0169, 0.0006 and 0.0405; 0.0014, 0.0003 and 0.1484; 0.0068, 7.61E-06 and 0.9398. h, i Control or MYC-overexpressing T24 cells were injected s.c. into the right flank of NSG mice. Tumor volume was measured at the indicated time points. Tumors were harvested and photographed on day 30 (h). In i, data were shown as the mean ± SD of five mice (n = 5). Two-way ANOVA (two-sided). P values based on the order of appearance: 0.0476 and 0.1463. Source data are provided in this paper. Similar results for f panel were obtained in three independent experiments.