Journal
CANCER CELL
Volume 37, Issue 1, Pages 37-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2019.11.003
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Funding
- National Institutes of Health (NIH)/National Cancer Institute (NCI) [5P30CA016087, P41 EB017183]
- Genome Technology Center [P30CA016087]
- Lung Cancer Research Foundation [NCI/NIH K99CA201618, K08CA222657, U01CA213333, P01 CA154303]
- Bridge Project
- Koch Institute for Integrative Cancer Research at MIT
- Dana-Farber/Harvard Cancer Center (DF/HCC)
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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.
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