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Discrete vulnerability to pharmacological CDK2 inhibition is governed by heterogeneity of the cancer cell cycle
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Discrete vulnerability to pharmacological CDK2 inhibition is governed by heterogeneity of the cancer cell cycle
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Journal Article
Discrete vulnerability to pharmacological CDK2 inhibition is governed by heterogeneity of the cancer cell cycle
2025
Overview
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.
It is becoming clear that heterogeneity in cancer cell cycles corresponds to variability of response to therapies targeting cyclin dependent kinases (CDKs). Here, the authors investigate CDK2-dependancy and response to CDK2 inhibition across different cancers, identifying markers of sensitivity and combinatorial therapeutic strategies.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/1
/ 13/106
/ 13/31
/ 13/89
/ 49/47
/ 49/98
/ Animals
/ Antineoplastic Agents - pharmacology
/ Breast Neoplasms - drug therapy
/ Breast Neoplasms - metabolism
/ Breast Neoplasms - pathology
/ Cancer
/ Cell Proliferation - drug effects
/ CRISPR
/ Cyclin-Dependent Kinase 2 - antagonists & inhibitors
/ Cyclin-Dependent Kinase 2 - genetics
/ Cyclin-Dependent Kinase 2 - metabolism
/ Cyclin-Dependent Kinase Inhibitor p16 - genetics
/ Cyclin-Dependent Kinase Inhibitor p16 - metabolism
/ Drug Resistance, Neoplasm - genetics
/ Female
/ Gene Expression Regulation, Neoplastic - drug effects
/ Humanities and Social Sciences
/ Humans
/ Kinases
/ Mice
/ Oncogene Proteins - genetics
/ Oncogene Proteins - metabolism
/ Protein Kinase Inhibitors - pharmacology
/ Science
/ Tumors
