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CDK7 inhibition potentiates genome instability triggering anti-tumor immunity in small cell lung cancer


Zhang, H; Christensen, CL; Dries, R; Oser, MG; Deng, J; Diskin, B; Li, F; Pan, Y; Zhang, X; Yin, Y; Papadopoulos, E; Pyon, V; Thakurdin, C; Kwiatkowski, N; Jani, K; Rabin, AR; Castro, DM; Chen, T; Silver, H; Huang, Q; Bulatovic, M; Dowling, CM; Sundberg, B; Leggett, A; Ranieri, M; Han, H; Li, S; Yang, A; Labbe, KE; Almonte, C; Sviderskiy, VO; QUINN, M; Donaghue, J; Wang, ES; Zhang, T; He, Z; Velcheti, V; Hammerman, PS; Freeman, GJ; Bonneau, R; Kaelin, WG, Jr; Sutherland, KD; Kersbergen, A; Aguirre, AJ; Yuan, GC; Rothenberg, E; Miller, G; Gray, NS; Wong, KK
2020-01-13
Cancer Cell
Journal Article
37
1
37-54 e9
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.
Cell Press
Cancer Biology and Stem Cells
10.1016/j.ccell.2019.11.003
31883968
Refer to copyright notice on published article.

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Creation Date 2020-01-21 11:05:22 Last Modified 2020-02-10 04:07:34