Castration‐resistant prostate cancer cells are addicted to the high activity of cyclin‐dependent kinase 2
- 1Department of Clinical Molecular Biology, EpiGen Institute of Clinical Medicine, University of Oslo Norway
- 2Department of Biochemistry and Developmental Biology, Faculty of Medicine University of Helsinki Finland
- 3EpiGen, Medical Division Akershus University Hospital Lørenskog Norway
Abstract
Cyclin‐dependent kinases (CDK) drive the progression through the cell cycle and thereby form classical targets for cancer therapy. Targeting androgen receptor (AR) is effective against prostate cancer (PC), but frequently leads to development of incurable castration‐resistant PC (CRPC). We show that emergence of CRPC is associated with significant upregulation of CDK2 cyclins and downregulation of CDK4/6 cyclins. This rewiring renders CRPC cells dependent on the high CDK2 activity, and CDK2‐specific inhibitors efficiently decrease proliferation of PC and CRPC cells. We develop a CDK2 inhibitor‐resistant CRPC model and perform a rational compound screen to assess which of the currently used anti‐CRPC treatments could augment CDK2 therapy‐response. This dual approach revealed that when our CRPC model acquired resistance to CDK2 inhibition, it increased AR signaling, and the combination of CDK2 inhibition with anti‐androgens induces synergistic antiproliferative effects on CRPC cells. Importantly, CDK2 inhibitors also show synergistic interaction with cell cycle poisons such as Docetaxel and Cisplatin, and combinatorial effects are also seen with radiotherapy, thereby offering multiple combinations against CRPC. In brief, we propose that CDK2 inhibition provides a rational basis for combinatorial therapy against CRPC.
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BibTeX
@article{chatterjee2026castrationresistant,
title = {{Castration‐resistant prostate cancer cells are addicted to the high activity of cyclin‐dependent kinase 2}},
author = {Joyeeta Chatterjee and Alessia Marin and Shivani Yalala and Harri M. Itkonen},
journal = {Molecular Oncology},
year = {2026},
month = sep,
doi = {10.1002/1878-0261.70319},
url = {https://doi.org/10.1002/1878-0261.70319},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Castration‐resistant prostate cancer cells are addicted to the high activity of cyclin‐dependent kinase 2
AU - Joyeeta Chatterjee
AU - Alessia Marin
AU - Shivani Yalala
AU - Harri M. Itkonen
PY - 2026
DA - 2026/09/02
JO - Molecular Oncology
DO - 10.1002/1878-0261.70319
UR - https://doi.org/10.1002/1878-0261.70319
AB - Cyclin‐dependent kinases (CDK) drive the progression through the cell cycle and thereby form classical targets for cancer therapy. Targeting androgen receptor (AR) is effective against prostate cancer (PC), but frequently leads to development of incurable castration‐resistant PC (CRPC). We show that emergence of CRPC is associated with significant upregulation of CDK2 cyclins and downregulation of CDK4/6 cyclins. This rewiring renders CRPC cells dependent on the high CDK2 activity, and CDK2‐specific inhibitors efficiently decrease proliferation of PC and CRPC cells. We develop a CDK2 inhibitor‐resistant CRPC model and perform a rational compound screen to assess which of the currently used anti‐CRPC treatments could augment CDK2 therapy‐response. This dual approach revealed that when our CRPC model acquired resistance to CDK2 inhibition, it increased AR signaling, and the combination of CDK2 inhibition with anti‐androgens induces synergistic antiproliferative effects on CRPC cells. Importantly, CDK2 inhibitors also show synergistic interaction with cell cycle poisons such as Docetaxel and Cisplatin, and combinatorial effects are also seen with radiotherapy, thereby offering multiple combinations against CRPC. In brief, we propose that CDK2 inhibition provides a rational basis for combinatorial therapy against CRPC.
SN - 1574-7891
SN - 1878-0261
ER -