@article{a2e2e7d46e184958a909e3ba7589f60a,
title = "CDK7 Inhibition Potentiates Genome Instability Triggering Anti-tumor Immunity in Small Cell Lung Cancer",
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",
author = "Hua Zhang and Christensen, {Camilla L.} and Ruben Dries and Oser, {Matthew G.} and Jiehui Deng and Brian Diskin and Fei Li and Yuanwang Pan and Xuzhu Zhang and Yandong Yin and Eleni Papadopoulos and Val Pyon and Cassandra Thakurdin and Nicholas Kwiatkowski and Kandarp Jani and Rabin, {Alexandra R.} and Castro, {Dayanne M.} and Ting Chen and Heather Silver and Qingyuan Huang and Mirna Bulatovic and Dowling, {Catr{\'i}ona M.} and Belen Sundberg and Alan Leggett and Michela Ranieri and Han Han and Shuai Li and Annan Yang and Labbe, {Kristen E.} and Christina Almonte and Sviderskiy, {Vladislav O.} and Max Quinn and Jack Donaghue and Wang, {Eric S.} and Tinghu Zhang and Zhixiang He and Vamsidhar Velcheti and Hammerman, {Peter S.} and Freeman, {Gordon J.} and Richard Bonneau and Kaelin, {William G.} and Sutherland, {Kate D.} and Ariena Kersbergen and Aguirre, {Andrew J.} and Yuan, {Guo Cheng} and Eli Rothenberg and George Miller and Gray, {Nathanael S.} and Wong, {Kwok Kin}",
note = "Funding Information: We thank the NYU Langone Health Preclinical Imaging Laboratory (partially funded by National Institutes of Health (NIH)/National Cancer Institute (NCI) 5P30CA016087 and NIH P41 EB017183) and the Genome Technology Center (partially supported by P30CA016087) for library preparation and sequencing. This work is supported by a Lung Cancer Research Foundation grant (H.Z.), NCI/NIH K99CA201618 (C.L.C.), K08CA222657 (M.G.O.), U01CA213333 (K.K.W. and N.S.G.), and P01 CA154303 (K.K.W.). This work is also supported by the Bridge Project (K.K.W. and N.S.G.), a collaboration between The Koch Institute for Integrative Cancer Research at MIT and the Dana-Farber/Harvard Cancer Center (DF/HCC). H.Z. C.L.C. R.D. N.S.G. and K.K.W. supervised the work, designed all the experiments, and interpreted the data. H.Z. C.L.C. R.D. M.G.O. J.D. B.D. F.L. Y.P. K.J. A.R.R. T.C. M.B. and C.M.D. conducted experiments. E.P. V.P. C.T. and H.S. performed MRI. R.D. D.M.C. G.-C.Y. and R.B. performed bioinformatics analysis. N.K. T.Z. and Z.H. contributed to compound synthesis. X.Z. Y.Y. and E.R. conducted single-cell imaging. H.Z. and K.E.L. conducted MRI analysis. M.G.O. V.O.S. G.M. K.D.S. A.K. A.J.A. and W.G.K. provided critical expertise and/or reagents. All the authors contributed to manuscript preparation. H.Z. C.L.C. R.D. and K.K.W. wrote the manuscript. K.K.W. is a founder and equity holder of G1 Therapeutics and has sponsored research agreements with MedImmune, Takeda, TargImmune, Bristol-Myers Squibb (BMS), Mirati, Merus, and Alkermes, and consulting and sponsored research agreements with AstraZeneca, Janssen, Pfizer, Novartis, Merck, Ono, and Array. N.G.S. is a founder, science advisory board member and equity holder in Gatekeeper, Syros, Petra, C4, B2S, and Soltego. The Gray lab receives or has received research funding from Novartis, Takeda, Astellas, Taiho, Janssen, Kinogen, Voronoi, Her2llc, Deerfield, and Sanofi. G.M. has research contract agreements with GlaxoSmithKline, Pfizer, and Puretech Health. V.V. has an advisory/consulting role at Genentech, Merck, BMS, Astrazeneca, Foundation Medicine, Nektar Therapeutics, Alkermes, Reddy labs, and Millennium pharma. M.G.O. is a consultant for HVH precision analytics, and has research funding from AstraZeneca and Eli Lilly and Company. H.Z. C.L.C. N.S.G. and K.K.W. have ownership interest in a patent application. Funding Information: We thank the NYU Langone Health Preclinical Imaging Laboratory (partially funded by National Institutes of Health (NIH)/National Cancer Institute ( NCI ) 5P30CA016087 and NIH P41 EB017183 ) and the Genome Technology Center (partially supported by P30CA016087 ) for library preparation and sequencing. This work is supported by a Lung Cancer Research Foundation grant (H.Z.), NCI/NIH K99CA201618 (C.L.C.), K08CA222657 (M.G.O.), U01CA213333 (K.K.W. and N.S.G.), and P01 CA154303 (K.K.W.). This work is also supported by the Bridge Project (K.K.W. and N.S.G.), a collaboration between The Koch Institute for Integrative Cancer Research at MIT and the Dana-Farber/Harvard Cancer Center (DF/HCC). Funding Information: K.K.W. is a founder and equity holder of G1 Therapeutics and has sponsored research agreements with MedImmune , Takeda , TargImmune , Bristol-Myers Squibb (BMS), Mirati , Merus , and Alkermes , and consulting and sponsored research agreements with AstraZeneca , Janssen , Pfizer , Novartis , Merck , Ono , and Array . N.G.S. is a founder, science advisory board member and equity holder in Gatekeeper, Syros, Petra, C4, B2S, and Soltego. The Gray lab receives or has received research funding from Novartis , Takeda , Astellas , Taiho , Janssen , Kinogen , Voronoi , Her2llc , Deerfield , and Sanofi . G.M. has research contract agreements with GlaxoSmithKline, Pfizer, and Puretech Health. V.V. has an advisory/consulting role at Genentech, Merck, BMS, Astrazeneca, Foundation Medicine, Nektar Therapeutics, Alkermes, Reddy labs, and Millennium pharma. M.G.O. is a consultant for HVH precision analytics, and has research funding from AstraZeneca and Eli Lilly and Company . H.Z., C.L.C., N.S.G., and K.K.W. have ownership interest in a patent application. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2020",
month = jan,
day = "13",
doi = "10.1016/j.ccell.2019.11.003",
language = "English (US)",
volume = "37",
pages = "37--54.e9",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "1",
}