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

Hua Zhang, Camilla L. Christensen, Ruben Dries, Matthew G. Oser, Jiehui Deng, Brian Diskin, Fei Li, Yuanwang Pan, Xuzhu Zhang, Yandong Yin, Eleni Papadopoulos, Val Pyon, Cassandra Thakurdin, Nicholas Kwiatkowski, Kandarp Jani, Alexandra R. Rabin, Dayanne M. Castro, Ting Chen, Heather Silver, Qingyuan HuangMirna Bulatovic, Catríona M. Dowling, Belen Sundberg, Alan Leggett, Michela Ranieri, Han Han, Shuai Li, Annan Yang, Kristen E. Labbe, Christina Almonte, Vladislav O. Sviderskiy, Max Quinn, Jack Donaghue, Eric S. Wang, Tinghu Zhang, Zhixiang He, Vamsidhar Velcheti, Peter S. Hammerman, Gordon J. Freeman, Richard Bonneau, William G. Kaelin, Kate D. Sutherland, Ariena Kersbergen, Andrew J. Aguirre, Guo Cheng Yuan, Eli Rothenberg, George Miller, Nathanael S. Gray, Kwok Kin Wong

Research output: Contribution to journalArticlepeer-review

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 languageEnglish (US)
Pages (from-to)37-54.e9
JournalCancer Cell
Volume37
Issue number1
DOIs
StatePublished - 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
  • Cell Biology
  • Cancer Research

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