Format

Send to

Choose Destination
Cancer Cell. 2020 Jan 13;37(1):37-54.e9. doi: 10.1016/j.ccell.2019.11.003. Epub 2019 Dec 26.

CDK7 Inhibition Potentiates Genome Instability Triggering Anti-tumor Immunity in Small Cell Lung Cancer.

Author information

1
Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY 10016, USA. Electronic address: hua.zhang@nyulangone.org.
2
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
3
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
4
Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY 10016, USA.
5
S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016, USA.
6
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
7
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
8
Departments of Biology and Computer Science, Center for Genomics and Systems Biology, New York University, New York, NY 10010, USA.
9
Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
10
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
11
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
12
Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3052, Australia.
13
Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
14
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
15
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA. Electronic address: nathanael_gray@dfci.harvard.edu.
16
Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY 10016, USA. Electronic address: kwok_kin.wong@nyulangone.org.

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

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center