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.
Original language | English (US) |
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Pages (from-to) | 37-54.e9 |
Journal | Cancer Cell |
Volume | 37 |
Issue number | 1 |
DOIs | |
State | Published - Jan 13 2020 |
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
ASJC Scopus subject areas
- Oncology
- Cancer Research