Discrete vulnerability to pharmacological CDK2 inhibition is governed by heterogeneity of the cancer cell cycle

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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Main Authors: 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
Format: Article
Language:English
Published: Nature Portfolio 2025-02-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-025-56674-4
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Summary: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.
ISSN:2041-1723

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