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 5

Therapeutic efficacy of CDK4/6i and CDK7i combination in TNBC models.

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Therapeutic efficacy of CDK4/6i and CDK7i combination in TNBC models. (A...
(A) Representative bright-field images of TNBC PDxO (HCI-002) treated with palbociclib (1 μM), SY5609 (50 nM), or their combination over time (n = 3 biological replicates). Scale bar: 100 μm. (B) Growth curve of PDxO (HCI-002) viability under indicated treatments. 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; **P ≤0.001; ***P ≤ 0.0001). (C and D) Tumor growth curves for MDA-MB-231 xenograft (C) and AT3OVA syngeneic (D) mouse models treated with vehicle, palbociclib (50 mg/kg), SY5609 (2 mg/kg), or the combination. Data are shown as means ± SEM (C: n = 12 mice for CDK4/6i+CDK7i, 8 mice for other groups; D: n = 7 mice/group). P values were calculated by 2-way ANOVA (C) or a mixed-effect model (D) with post hoc Tukey’s test (*P ≤ 0.05; ***P ≤ 0.0001). (E) Box plot of tumor mass for AT3OVA tumors. The middle line indicates the median, with box edges representing interquartile ranges (n = 7 mice/group). P values were calculated by 1-way ANOVA with post hoc Tukey’s test (*P ≤ 0.05; ***P ≤ 0.0001). (F and G) Tumor growth curves for AT3OVA model in immunocompetent (C57BL/6J) or -deficient (J:NU) mice. Mice were treated with either vehicle or a combination of palbociclib (50 mg/kg) and SY5609 (2 mg/kg). Data are presented as mean ± SEM (n = 5 mice/group) (F). P values were calculated by a mixed-effect model with post hoc Tukey’s test (*P ≤ 0.05; **P ≤ 0.001; ***P ≤ 0.0001).