Abstract
Cyclin-dependent kinase 7 (CDK7) is a central regulator of the cell cycle and gene transcription. However, little is known about its impact on genomic instability and cancer immunity. Using a selective CDK7 inhibitor, YKL-5-124, we demonstrated that CDK7 inhibition predominately disrupts cell-cycle progression and induces DNA replication stress and genome instability in small cell lung cancer (SCLC) while simultaneously triggering immune-response signaling. These tumor-intrinsic events provoke a robust immune surveillance program elicited by T cells, which is further enhanced by the addition of immune-checkpoint blockade. Combining YKL-5-124 with anti-PD-1 offers significant survival benefit in multiple highly aggressive murine models of SCLC, providing a rationale for new combination regimens consisting of CDK7 inhibitors and immunotherapies.
Keywords:
CDK7; YKL-5-124; anti-tumor immunity; cell cycle; genome instability; immune checkpoint blockade; immunotherapy; replication stress; single-cell analysis; small cell lung cancer.
Copyright © 2019 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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CD4-Positive T-Lymphocytes / cytology
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CD8-Positive T-Lymphocytes / cytology
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Chemokine CXCL9 / metabolism
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Cyclin-Dependent Kinase-Activating Kinase
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Cyclin-Dependent Kinases / antagonists & inhibitors*
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Cyclin-Dependent Kinases / genetics*
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DNA Damage
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Female
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Genomic Instability*
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Humans
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Immune System
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Inflammation
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Interferon-gamma / metabolism
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Lung Neoplasms / drug therapy
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Lung Neoplasms / genetics*
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Lung Neoplasms / immunology
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Male
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Mice
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Micronucleus Tests
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Programmed Cell Death 1 Receptor / antagonists & inhibitors
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Pyrazoles / pharmacology
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Pyrroles / pharmacology
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Signal Transduction
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Small Cell Lung Carcinoma / drug therapy
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Small Cell Lung Carcinoma / genetics*
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Small Cell Lung Carcinoma / immunology
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Antineoplastic Agents
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CXCL9 protein, human
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Chemokine CXCL9
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IFNG protein, human
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PDCD1 protein, human
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Programmed Cell Death 1 Receptor
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Pyrazoles
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Pyrroles
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Tumor Necrosis Factor-alpha
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YKL-5-124
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Interferon-gamma
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Cyclin-Dependent Kinases
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Cyclin-Dependent Kinase-Activating Kinase