Dual targeting of CDK4/6 and CDK7 augments tumor response and antitumor immunity in breast cancer models
Sungsoo Kim, Eugene Son, Ha-Ram Park, Minah Kim, Hee Won Yang
Sungsoo Kim, Eugene Son, Ha-Ram Park, Minah Kim, Hee Won Yang
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Research Article Cell biology Oncology

Dual targeting of CDK4/6 and CDK7 augments tumor response and antitumor immunity in breast cancer models

Abstract

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have transformed the treatment landscape for hormone receptor+ (HR+) breast cancer. However, their long-term efficacy is limited by acquired resistance, and CDK4/6i monotherapy remains ineffective in triple-negative breast cancer (TNBC). Here, we demonstrate that dual inhibition of CDK4/6 and CDK7 is a promising strategy to overcome therapeutic resistance in both HR+ and TNBC models. Kinetic analyses revealed that CDK7 inhibitors (CDK7i) primarily impair RNA polymerase II–mediated transcription rather than directly targeting cell cycle CDKs. This transcriptional suppression attenuated E2F-driven transcriptional amplification, a key mechanism for developing CDK4/6i resistance following the degradation of the retinoblastoma protein. Consequently, combining CDK7i at minimal effective concentrations with CDK4/6i potently inhibited the growth of drug-resistant tumors. Furthermore, dual CDK4/6 and CDK7 inhibition stimulated immune-related signaling and cytokine production in cancer cells, promoting antitumor immune responses within the tumor microenvironment. These findings provide mechanistic insights into CDK inhibition and support the therapeutic potential of combining CDK7i with CDK4/6i for breast cancer treatment.

Authors

Sungsoo Kim, Eugene Son, Ha-Ram Park, Minah Kim, Hee Won Yang

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Figure 2

Synergistic inhibition of persister cell development and resistance by combined CDK4/6i and CDK7i.

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Synergistic inhibition of persister cell development and resistance by c...
(A) Dot plot of enriched reactome gene sets in persister versus non-persister MDA-MB-231 cells after 14 days of palbociclib (1 μM) treatment. Significant enriched pathways were defined as adjusted P < 0.05 and FDR < 0.25. Dot size indicates gene count, and color indicates adjusted P values. (B) GSEA plot showing increased RNA polymerase II signaling in persister cells relative to non-persister cells. Normalized enrichment score (NES) and q values are shown. (C) Synergy analysis of palbociclib and SY5609. Synergy scores ± 95% CIs were calculated using the Bliss independence model (n = 3 biological replicates). (D and E) Heatmaps of single-cell CDK4/6 and CDK2 activity traces in MDA-MB-231 cells treated with palbociclib (1 μM) alone (D) or in combination with SY5609 (50 nM) (E). Percentages denote the proportion of persister cells (CDK2 activity > 1.0 for over 4 h during 30–48 h after treatment). (F) Quantification of persister cells in MDA-MB-231 and MCF-7 cells across treatment conditions. Data are shown as means ± SD (n = 3 biological replicates). P values were calculated by 1-way ANOVA with post hoc Tukey’s test (*P ≤ 0.05; ***P ≤ 0.0001). (G) Immunoblot analysis of Rb and β-actin in cells treated with DMSO, palbociclib (1 μM), or palbociclib + SY5609 (50 nM) for 48 h. (H) Representative clonogenic assay showing colony formation after 28-day treatment with palbociclib (1 μM), SY5609 (50 nM), or their combination (n = 3 biological replicates). (I) Quantification of colony area (%) across treatments. Data are shown as means ± SD (n = 3 biological replicates). P values were calculated by 1-way ANOVA with post hoc Tukey’s test (*P ≤ 0.05; **P ≤ 0.001; ***P ≤ 0.0001).