TY - JOUR
T1 - Disrupting CDK9 activity suppresses triple-negative breast cancer and is enhanced by EGFR Inhibition
AU - van der Noord, Vera E.
AU - McLaughlin, Ronan P.
AU - Karuntu, Jessica S.
AU - He, Jichao
AU - Timmermans, A. Mieke
AU - Basnet, Sunita K.C.
AU - Long, Yi
AU - Diab, Sarah Al Haj
AU - Tadesse, Solomon
AU - Proost, Natalie
AU - van Gerwen, Bastiaan
AU - Siteur, Bjørn
AU - van de Ven, Marieke
AU - Pont, Chantal
AU - Le Dévédec, Sylvia E.
AU - Martens, John W.M.
AU - Wang, Shudong
AU - Zhang, Yinghui
AU - van de Water, Bob
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2026/1/8
Y1 - 2026/1/8
N2 - Purpose: CDK9, in complex with cyclin T1 or T2, is essential for mRNA transcription by enabling paused RNA polymerase II to proceed into elongation. Increasing evidence highlights CDK9’s involvement in transcriptional addiction in cancer. Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype for which effective targeted therapies remain limited. Here, we aimed to define the therapeutic potential of novel CDK9 inhibitors in TNBC.Methods: We explored the efficacy and mechanism of action of novel CDK9 inhibitors, alone or in combination with EGFR inhibitors, using TNBC cell lines and in vivo xenograft models. Results: Targeting CDK9 significantly impaired proliferation and induced apoptosis in multiple TNBC cell lines. Transcriptomic analyses revealed that CDK9 inhibitors induced downregulation of genes involved in transcription, cell cycle progression, and oncogenic signalling pathways, including TGF-β and Wnt/β-catenin signalling. Combined CDK9 and EGFR inhibition disrupted transcriptional programs, enhanced TNBC cell death in vitro, and acted synergistically to reduce tumour growth in PDX and Hs578T xenograft models, although this combination was also associated with increased toxicity. Conclusion: Our results position CDK9 as a promising therapeutic target in TNBC, either alone or in combination with EGFR inhibition, provided that side effects associated with this combination treatment can be controlled.
AB - Purpose: CDK9, in complex with cyclin T1 or T2, is essential for mRNA transcription by enabling paused RNA polymerase II to proceed into elongation. Increasing evidence highlights CDK9’s involvement in transcriptional addiction in cancer. Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype for which effective targeted therapies remain limited. Here, we aimed to define the therapeutic potential of novel CDK9 inhibitors in TNBC.Methods: We explored the efficacy and mechanism of action of novel CDK9 inhibitors, alone or in combination with EGFR inhibitors, using TNBC cell lines and in vivo xenograft models. Results: Targeting CDK9 significantly impaired proliferation and induced apoptosis in multiple TNBC cell lines. Transcriptomic analyses revealed that CDK9 inhibitors induced downregulation of genes involved in transcription, cell cycle progression, and oncogenic signalling pathways, including TGF-β and Wnt/β-catenin signalling. Combined CDK9 and EGFR inhibition disrupted transcriptional programs, enhanced TNBC cell death in vitro, and acted synergistically to reduce tumour growth in PDX and Hs578T xenograft models, although this combination was also associated with increased toxicity. Conclusion: Our results position CDK9 as a promising therapeutic target in TNBC, either alone or in combination with EGFR inhibition, provided that side effects associated with this combination treatment can be controlled.
UR - https://www.scopus.com/pages/publications/105026966553
U2 - 10.1007/s13402-025-01154-6
DO - 10.1007/s13402-025-01154-6
M3 - Article
C2 - 41505030
AN - SCOPUS:105026966553
SN - 2211-3428
VL - 49
JO - Cellular Oncology
JF - Cellular Oncology
IS - 1
M1 - 20
ER -
