Discrete vulnerability to pharmacological CDK2 inhibition is governed by heterogeneity of the cancer cell cycle
Abstract Cyclin dependent kinase 2 (CDK2) regulates cell cycle and is an emerging target for cancer therapy. There are relatively small numbers of tumor models that exhibit strong dependence on CDK2 and undergo G1 cell cycle arrest following CDK2 inhibition. The expression of P16INK4A and cyclin E1...
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| Format: | Article |
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56674-4 |
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| author | Vishnu Kumarasamy Jianxin Wang Michelle Roti Yin Wan Adam P. Dommer Hanna Rosenheck Sivasankar Putta Alec Trub John Bisi Jay Strum Patrick Roberts Seth M. Rubin Costakis Frangou Karen McLean Agnieszka K. Witkiewicz Erik S. Knudsen |
| author_facet | Vishnu Kumarasamy Jianxin Wang Michelle Roti Yin Wan Adam P. Dommer Hanna Rosenheck Sivasankar Putta Alec Trub John Bisi Jay Strum Patrick Roberts Seth M. Rubin Costakis Frangou Karen McLean Agnieszka K. Witkiewicz Erik S. Knudsen |
| author_sort | Vishnu Kumarasamy |
| collection | DOAJ |
| description | Abstract Cyclin dependent kinase 2 (CDK2) regulates cell cycle and is an emerging target for cancer therapy. There are relatively small numbers of tumor models that exhibit strong dependence on CDK2 and undergo G1 cell cycle arrest following CDK2 inhibition. The expression of P16INK4A and cyclin E1 determines this sensitivity to CDK2 inhibition. The co-expression of these genes occurs in breast cancer patients highlighting their clinical significance as predictive biomarkers for CDK2-targeted therapies. In cancer models that are genetically independent of CDK2, pharmacological inhibitors suppress cell proliferation by inducing 4N cell cycle arrest and increasing the expressions of phospho-CDK1 (Y15) and cyclin B1. CRISPR screens identify CDK2 loss as a mediator of resistance to a CDK2 inhibitor, INX-315. Furthermore, CDK2 deletion reverses the G2/M block induced by CDK2 inhibitors and restores cell proliferation. Complementary drug screens define multiple means to cooperate with CDK2 inhibition beyond G1/S. These include the depletion of mitotic regulators as well as CDK4/6 inhibitors cooperate with CDK2 inhibition in multiple phases of the cell cycle. Overall, this study underscores two fundamentally distinct features of response to CDK2 inhibitors that are conditioned by tumor context and could serve as the basis for differential therapeutic strategies in a wide range of cancers. |
| format | Article |
| id | doaj-art-a7354fd0d62842a483cf0dff9e6fb1b9 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-a7354fd0d62842a483cf0dff9e6fb1b92025-02-09T12:45:40ZengNature PortfolioNature Communications2041-17232025-02-0116112110.1038/s41467-025-56674-4Discrete vulnerability to pharmacological CDK2 inhibition is governed by heterogeneity of the cancer cell cycleVishnu Kumarasamy0Jianxin Wang1Michelle Roti2Yin Wan3Adam P. Dommer4Hanna Rosenheck5Sivasankar Putta6Alec Trub7John Bisi8Jay Strum9Patrick Roberts10Seth M. Rubin11Costakis Frangou12Karen McLean13Agnieszka K. Witkiewicz14Erik S. Knudsen15Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer CenterDepartment of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer CenterDepartment of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer CenterDepartment of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer CenterDepartment of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer CenterDepartment of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer CenterDepartment of Chemistry and Biochemistry, University of California Santa CruzIncyclix BioIncyclix BioIncyclix BioIncyclix BioDepartment of Chemistry and Biochemistry, University of California Santa CruzDepartment of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer CenterDepartment of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer CenterDepartment of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer CenterDepartment of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer CenterAbstract Cyclin dependent kinase 2 (CDK2) regulates cell cycle and is an emerging target for cancer therapy. There are relatively small numbers of tumor models that exhibit strong dependence on CDK2 and undergo G1 cell cycle arrest following CDK2 inhibition. The expression of P16INK4A and cyclin E1 determines this sensitivity to CDK2 inhibition. The co-expression of these genes occurs in breast cancer patients highlighting their clinical significance as predictive biomarkers for CDK2-targeted therapies. In cancer models that are genetically independent of CDK2, pharmacological inhibitors suppress cell proliferation by inducing 4N cell cycle arrest and increasing the expressions of phospho-CDK1 (Y15) and cyclin B1. CRISPR screens identify CDK2 loss as a mediator of resistance to a CDK2 inhibitor, INX-315. Furthermore, CDK2 deletion reverses the G2/M block induced by CDK2 inhibitors and restores cell proliferation. Complementary drug screens define multiple means to cooperate with CDK2 inhibition beyond G1/S. These include the depletion of mitotic regulators as well as CDK4/6 inhibitors cooperate with CDK2 inhibition in multiple phases of the cell cycle. Overall, this study underscores two fundamentally distinct features of response to CDK2 inhibitors that are conditioned by tumor context and could serve as the basis for differential therapeutic strategies in a wide range of cancers.https://doi.org/10.1038/s41467-025-56674-4 |
| spellingShingle | Vishnu Kumarasamy Jianxin Wang Michelle Roti Yin Wan Adam P. Dommer Hanna Rosenheck Sivasankar Putta Alec Trub John Bisi Jay Strum Patrick Roberts Seth M. Rubin Costakis Frangou Karen McLean Agnieszka K. Witkiewicz Erik S. Knudsen Discrete vulnerability to pharmacological CDK2 inhibition is governed by heterogeneity of the cancer cell cycle Nature Communications |
| title | Discrete vulnerability to pharmacological CDK2 inhibition is governed by heterogeneity of the cancer cell cycle |
| title_full | Discrete vulnerability to pharmacological CDK2 inhibition is governed by heterogeneity of the cancer cell cycle |
| title_fullStr | Discrete vulnerability to pharmacological CDK2 inhibition is governed by heterogeneity of the cancer cell cycle |
| title_full_unstemmed | Discrete vulnerability to pharmacological CDK2 inhibition is governed by heterogeneity of the cancer cell cycle |
| title_short | Discrete vulnerability to pharmacological CDK2 inhibition is governed by heterogeneity of the cancer cell cycle |
| title_sort | discrete vulnerability to pharmacological cdk2 inhibition is governed by heterogeneity of the cancer cell cycle |
| url | https://doi.org/10.1038/s41467-025-56674-4 |
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