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 1

Impact of CDK7i and CDK inhibitor monotherapies on breast cancer.

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Impact of CDK7i and CDK inhibitor monotherapies on breast cancer. (A) IC...
(A) IC50 of CDK7i SY5609 and LDC4297 on mRNA transcription rates, CDK2 and CDK4/6 activities, and the percentage of S phase cells in MDA-MB-231 and MCF-7 cells following 48 h treatment. 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). (B) Violin plots of EU incorporation in MDA-MB-231 cells treated with either SY5609 (50 nM) or LDC4297 (50 nM). Cells were randomly selected for 1,000 cells per condition in each replicate. Data are shown as means ± SD (n = 3 biological replicates). P values were calculated by 2-way ANOVA with post hoc Tukey’s test (*P ≤ 0.05). (C) Averaged live-cell traces of CDK4/6 and CDK2 activity in MDA-MB-231 cells treated with DMSO, SY5609 (50 nM), LDC4297 (50 nM), palbociclib (1 μM), tagtociclib (5 μM), or palbociclib + tagtociclib. Data are shown as mean ± 95% CIs (n > 1,800 cells/condition). (D) Tumor growth curves of AT3OVA syngeneic mouse models treated with vehicle or increasing doses of SY5609 (2, 5, 10, or 25 mg/kg). Data are shown as means ± SEM (n = 5 mice/group). P values were calculated by a mixed-effect model (*P ≤ 0.05; **P ≤ 0.001; ***P ≤ 0.0001). (E and F) Individual (E) and final (F) tumor volumes of AT3OVA-bearing C57BL/6J mice treated with vehicle, palbociclib (50 mg/kg), tagtociclib (50 mg/kg), or SY5609 (10 mg/kg).