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Cancer Cell
Journal Prestige (SJR): 12.7
Citation Impact (citeScore): 15
Number of Followers: 83  
 
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ISSN (Print) 1535-6108
Published by Elsevier Homepage  [3206 journals]
  • CDK4/6 Inhibitors Impair Recovery from Cytotoxic Chemotherapy in
           Pancreatic Adenocarcinoma
    • Abstract: Publication date: Available online 27 February 2020Source: Cancer CellAuthor(s): Beatriz Salvador-Barbero, Mónica Álvarez-Fernández, Elisabet Zapatero-Solana, Aicha El Bakkali, María del Camino Menéndez, Pedro P. López-Casas, Tomas Di Domenico, Tao Xie, Todd VanArsdale, David J. Shields, Manuel Hidalgo, Marcos Malumbres
       
  • Proteome Instability Is a Therapeutic Vulnerability in Mismatch
           Repair-Deficient Cancer
    • Abstract: Publication date: Available online 27 February 2020Source: Cancer CellAuthor(s): Daniel J. McGrail, Jeannine Garnett, Jun Yin, Hui Dai, David J.H. Shih, Truong Nguyen Anh Lam, Yang Li, Chaoyang Sun, Yongsheng Li, Rosemarie Schmandt, Ji Yuan Wu, Limei Hu, Yulong Liang, Guang Peng, Eric Jonasch, David Menter, Melinda S. Yates, Scott Kopetz, Karen H. Lu, Russell Broaddus
       
  • Hyperactivation of TORC1 Drives Resistance to the Pan-HER Tyrosine Kinase
           Inhibitor Neratinib in HER2-Mutant Cancers
    • Abstract: Publication date: 10 February 2020Source: Cancer Cell, Volume 37, Issue 2Author(s): Dhivya R. Sudhan, Angel Guerrero-Zotano, Helen Won, Paula González Ericsson, Alberto Servetto, Mariela Huerta-Rosario, Dan Ye, Kyung-min Lee, Luigi Formisano, Yan Guo, Qi Liu, Lisa N. Kinch, Monica Red Brewer, Teresa Dugger, James Koch, Michael J. Wick, Richard E. Cutler, Alshad S. Lalani, Richard Bryce, Alan Auerbach
       
  • Comparative Molecular Life History of Spontaneous Canine and Human Gliomas
    • Abstract: Publication date: 10 February 2020Source: Cancer Cell, Volume 37, Issue 2Author(s): Samirkumar B. Amin, Kevin J. Anderson, C. Elizabeth Boudreau, Emmanuel Martinez-Ledesma, Emre Kocakavuk, Kevin C. Johnson, Floris P. Barthel, Frederick S. Varn, Cynthia Kassab, Xiaoyang Ling, Hoon Kim, Mary Barter, Ching C. Lau, Chew Yee Ngan, Margaret Chapman, Jennifer W. Koehler, James P. Long, Andrew D. Miller, C. Ryan Miller, Brian F. PorterSummarySporadic gliomas in companion dogs provide a window on the interaction between tumorigenic mechanisms and host environment. We compared the molecular profiles of canine gliomas with those of human pediatric and adult gliomas to characterize evolutionarily conserved mammalian mutational processes in gliomagenesis. Employing whole-genome, exome, transcriptome, and methylation sequencing of 83 canine gliomas, we found alterations shared between canine and human gliomas such as the receptor tyrosine kinases, TP53 and cell-cycle pathways, and IDH1 R132. Canine gliomas showed high similarity with human pediatric gliomas per robust aneuploidy, mutational rates, relative timing of mutations, and DNA-methylation patterns. Our cross-species comparative genomic analysis provides unique insights into glioma etiology and the chronology of glioma-causing somatic alterations.Graphical Graphical abstract for this article
       
  • The Repertoire of Serous Ovarian Cancer Non-genetic Heterogeneity Revealed
           by Single-Cell Sequencing of Normal Fallopian Tube Epithelial Cells
    • Abstract: Publication date: 10 February 2020Source: Cancer Cell, Volume 37, Issue 2Author(s): Zhiyuan Hu, Mara Artibani, Abdulkhaliq Alsaadi, Nina Wietek, Matteo Morotti, Tingyan Shi, Zhe Zhong, Laura Santana Gonzalez, Salma El-Sahhar, Mohammad KaramiNejadRanjbar, Garry Mallett, Yun Feng, Kenta Masuda, Yiyan Zheng, Kay Chong, Stephen Damato, Sunanda Dhar, Leticia Campo, Riccardo Garruto Campanile, Hooman Soleymani majdSummaryThe inter-differentiation between cell states promotes cancer cell survival under stress and fosters non-genetic heterogeneity (NGH). NGH is, therefore, a surrogate of tumor resilience but its quantification is confounded by genetic heterogeneity. Here we show that NGH in serous ovarian cancer (SOC) can be accurately measured when informed by the molecular signatures of the normal fallopian tube epithelium (FTE) cells, the cells of origin of SOC. Surveying the transcriptomes of ∼6,000 FTE cells, predominantly from non-ovarian cancer patients, identified 6 FTE subtypes. We used subtype signatures to deconvolute SOC expression data and found substantial intra-tumor NGH. Importantly, NGH-based stratification of ∼1,700 tumors robustly correlated with survival. Our findings lay the foundation for accurate prognostic and therapeutic stratification of SOC.
       
  • Direct Phosphorylation and Stabilization of MYC by Aurora B Kinase Promote
           T-cell Leukemogenesis
    • Abstract: Publication date: 10 February 2020Source: Cancer Cell, Volume 37, Issue 2Author(s): Jue Jiang, Jingchao Wang, Ming Yue, Xiaolian Cai, Tianci Wang, Chao Wu, Hexiu Su, Yanwu Wang, Meng Han, Yingchi Zhang, Xiaofan Zhu, Peng Jiang, Peng Li, Yonghua Sun, Wuhan Xiao, Hui Feng, Guoliang Qing, Hudan LiuSummaryDeregulation of MYC plays an essential role in T cell acute lymphoblastic leukemia (T-ALL), yet the mechanisms underlying its deregulation remain elusive. Herein, we identify a molecular mechanism responsible for reciprocal activation between Aurora B kinase (AURKB) and MYC. AURKB directly phosphorylates MYC at serine 67, counteracting GSK3β-directed threonine 58 phosphorylation and subsequent FBXW7-mediated proteasomal degradation. Stabilized MYC, in concert with T cell acute lymphoblastic leukemia 1 (TAL1), directly activates AURKB transcription, constituting a positive feedforward loop that reinforces MYC-regulated oncogenic programs. Therefore, inhibitors of AURKB induce prominent MYC degradation concomitant with robust leukemia cell death. These findings reveal an AURKB-MYC regulatory circuit that underlies T cell leukemogenesis, and provide a rationale for therapeutic targeting of oncogenic MYC via AURKB inhibition.Graphical Graphical abstract for this article
       
  • Emerging Roles for Branched-Chain Amino Acid Metabolism in Cancer
    • Abstract: Publication date: 10 February 2020Source: Cancer Cell, Volume 37, Issue 2Author(s): Sharanya Sivanand, Matthew G. Vander HeidenMetabolic pathways must be adapted to support cell processes required for transformation and cancer progression. Amino acid metabolism is deregulated in many cancers, with changes in branched-chain amino acid metabolism specifically affecting cancer cell state as well as systemic metabolism in individuals with malignancy. This review highlights key concepts surrounding the current understanding of branched-chain amino acid metabolism and its role in cancer.
       
  • THEMIS-SHP1 Recruitment by 4-1BB Tunes LCK-Mediated Priming of Chimeric
           Antigen Receptor-Redirected T Cells
    • Abstract: Publication date: Available online 30 January 2020Source: Cancer CellAuthor(s): Chuang Sun, Peishun Shou, Hongwei Du, Koichi Hirabayashi, Yuhui Chen, Laura E. Herring, Sarah Ahn, Yang Xu, Kyogo Suzuki, Guangming Li, Ourania Tsahouridis, Lishan Su, Barbara Savoldo, Gianpietro DottiSummaryChimeric antigen receptor (CAR) T cell costimulation mediated by CD28 and 4-1BB is essential for CAR-T cell-induced tumor regression. However, CD28 and 4-1BB differentially modulate kinetics, metabolism and persistence of CAR-T cells, and the mechanisms governing these differences are not fully understood. We found that LCK recruited into the synapse of CD28-encoding CAR by co-receptors causes antigen-independent CAR-CD3ζ phosphorylation and increased antigen-dependent T cell activation. In contrast, the synapse formed by 4-1BB-encoding CAR recruits the THEMIS-SHP1 phosphatase complex that attenuates CAR-CD3ζ phosphorylation. We further demonstrated that the CAR synapse can be engineered to recruit either LCK to enhance the kinetics of tumor killing of 4-1BB CAR-T cells or SHP1 to tune down cytokine release of CD28 CAR-T cells.Graphical Graphical abstract for this article
       
  • EZH2 Inhibition Sensitizes CARM1-High, Homologous Recombination Proficient
           Ovarian Cancers to PARP Inhibition
    • Abstract: Publication date: Available online 30 January 2020Source: Cancer CellAuthor(s): Sergey Karakashev, Takeshi Fukumoto, Bo Zhao, Jianhuang Lin, Shuai Wu, Nail Fatkhutdinov, Pyoung-Hwa Park, Galina Semenova, Stephanie Jean, Mark G. Cadungog, Mark E. Borowsky, Andrew V. Kossenkov, Qin Liu, Rugang ZhangSummaryIn response to DNA double-strand breaks, MAD2L2-containing shieldin complex plays a critical role in the choice between homologous recombination (HR) and non-homologous end-joining (NHEJ)-mediated repair. Here we show that EZH2 inhibition upregulates MAD2L2 and sensitizes HR-proficient epithelial ovarian cancer (EOC) to poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor in a CARM1-dependent manner. CARM1 promotes MAD2L2 silencing by driving the switch from the SWI/SNF complex to EZH2 through methylating the BAF155 subunit of the SWI/SNF complex on the MAD2L2 promoter. EZH2 inhibition upregulates MAD2L2 to decrease DNA end resection, which increases NHEJ and chromosomal abnormalities, ultimately causing mitotic catastrophe in PARP inhibitor treated HR-proficient cells. Significantly, EZH2 inhibitor sensitizes CARM1-high, but not CARM-low, EOCs to PARP inhibitors in both orthotopic and patient-derived xenografts.Graphical Graphical abstract for this article
       
  • Dynamic ROS Control by TIGAR Regulates the Initiation and Progression of
           Pancreatic Cancer
    • Abstract: Publication date: Available online 23 January 2020Source: Cancer CellAuthor(s): Eric C. Cheung, Gina M. DeNicola, Colin Nixon, Karen Blyth, Christiaan F. Labuschagne, David A. Tuveson, Karen H. VousdenSummaryThe TIGAR protein has antioxidant activity that supports intestinal tissue repair and adenoma development. Using a pancreatic ductal adenocarcinoma (PDAC) model, we show that reactive oxygen species (ROS) regulation by TIGAR supports premalignant tumor initiation while restricting metastasis. Increased ROS in PDAC cells drives a phenotypic switch that increases migration, invasion, and metastatic capacity. This switch is dependent on increased activation of MAPK signaling and can be reverted by antioxidant treatment. In mouse and human, TIGAR expression is modulated during PDAC development, with higher TIGAR levels in premalignant lesions and lower TIGAR levels in metastasizing tumors. Our study indicates that temporal, dynamic control of ROS underpins full malignant progression and helps to rationalize conflicting reports of pro- and anti-tumor effects of antioxidant treatment.Graphical Graphical abstract for this article
       
  • Hyperactivation of TORC1 Drives Resistance to the Pan-HER Tyrosine Kinase
           Inhibitor Neratinib in HER2-Mutant Cancers
    • Abstract: Publication date: Available online 23 January 2020Source: Cancer CellAuthor(s): Dhivya R. Sudhan, Angel Guerrero-Zotano, Helen Won, Paula González Ericsson, Alberto Servetto, Mariela Huerta-Rosario, Dan Ye, Kyung-min Lee, Luigi Formisano, Yan Guo, Qi Liu, Lisa N. Kinch, Monica Red Brewer, Teresa Dugger, James Koch, Michael J. Wick, Richard E. Cutler, Alshad S. Lalani, Richard Bryce, Alan AuerbachSummaryWe developed neratinib-resistant HER2-mutant cancer cells by gradual dose escalation. RNA sequencing identified TORC1 signaling as an actionable mechanism of drug resistance. Primary and acquired neratinib resistance in HER2-mutant breast cancer patient-derived xenografts (PDXs) was also associated with TORC1 hyperactivity. Genetic suppression of RAPTOR or RHEB ablated P-S6 and restored sensitivity to the tyrosine kinase inhibitor. The combination of the TORC1 inhibitor everolimus and neratinib potently arrested the growth of neratinib-resistant xenografts and organoids established from neratinib-resistant PDXs. RNA and whole-exome sequencing revealed RAS-mediated TORC1 activation in a subset of neratinib-resistant models. DNA sequencing of HER2-mutant tumors clinically refractory to neratinib, as well as circulating tumor DNA profiling of patients who progressed on neratinib, showed enrichment of genomic alterations that converge to activate the mTOR pathway.Graphical Graphical abstract for this article
       
  • Science that Inspires
    • Abstract: Publication date: Available online 23 January 2020Source: Cancer CellAuthor(s): The Cell Press Team
       
  • Loss or Inhibition of Stromal-Derived PlGF Prolongs Survival of Mice with
           Imatinib-Resistant Bcr-Abl1+ Leukemia
    • Abstract: Publication date: 13 January 2020Source: Cancer Cell, Volume 37, Issue 1Author(s): Thomas Schmidt, Behzad Kharabi Masouleh, Sonja Loges, Sandra Cauwenberghs, Peter Fraisl, Christa Maes, Bart Jonckx, Kim De Keersmaecker, Maria Kleppe, Marc Tjwa, Thomas Schenk, Stefan Vinckier, Rita Fragoso, Maria De Mol, Karolien Beel, Sérgio Dias, Catherine Verfaillie, Richard E. Clark, Tim H. Brümmendorf, Peter Vandenberghe
       
  • Treatment-Induced Tumor Dormancy through YAP-Mediated Transcriptional
           Reprogramming of the Apoptotic Pathway
    • Abstract: Publication date: 13 January 2020Source: Cancer Cell, Volume 37, Issue 1Author(s): Kari J. Kurppa, Yao Liu, Ciric To, Tinghu Zhang, Mengyang Fan, Amir Vajdi, Erik H. Knelson, Yingtian Xie, Klothilda Lim, Paloma Cejas, Andrew Portell, Patrick H. Lizotte, Scott B. Ficarro, Shuai Li, Ting Chen, Heidi M. Haikala, Haiyun Wang, Magda Bahcall, Yang Gao, Sophia ShalhoutSummaryEradicating tumor dormancy that develops following epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment of EGFR-mutant non-small cell lung cancer, is an attractive therapeutic strategy but the mechanisms governing this process are poorly understood. Blockade of ERK1/2 reactivation following EGFR TKI treatment by combined EGFR/MEK inhibition uncovers cells that survive by entering a senescence-like dormant state characterized by high YAP/TEAD activity. YAP/TEAD engage the epithelial-to-mesenchymal transition transcription factor SLUG to directly repress pro-apoptotic BMF, limiting drug-induced apoptosis. Pharmacological co-inhibition of YAP and TEAD, or genetic deletion of YAP1, all deplete dormant cells by enhancing EGFR/MEK inhibition-induced apoptosis. Enhancing the initial efficacy of targeted therapies could ultimately lead to prolonged treatment responses in cancer patients.Graphical Graphical abstract for this article
       
  • Myosin II Reactivation and Cytoskeletal Remodeling as a Hallmark and a
           Vulnerability in Melanoma Therapy Resistance
    • Abstract: Publication date: 13 January 2020Source: Cancer Cell, Volume 37, Issue 1Author(s): Jose L. Orgaz, Eva Crosas-Molist, Amine Sadok, Anna Perdrix-Rosell, Oscar Maiques, Irene Rodriguez-Hernandez, Jo Monger, Silvia Mele, Mirella Georgouli, Victoria Bridgeman, Panagiotis Karagiannis, Rebecca Lee, Pahini Pandya, Lena Boehme, Fredrik Wallberg, Chris Tape, Sophia N. Karagiannis, Ilaria Malanchi, Victoria Sanz-MorenoSummaryDespite substantial clinical benefit of targeted and immune checkpoint blockade-based therapies in melanoma, resistance inevitably develops. We show cytoskeletal remodeling and changes in expression and activity of ROCK-myosin II pathway during acquisition of resistance to MAPK inhibitors. MAPK regulates myosin II activity, but after initial therapy response, drug-resistant clones restore myosin II activity to increase survival. High ROCK-myosin II activity correlates with aggressiveness, identifying targeted therapy- and immunotherapy-resistant melanomas. Survival of resistant cells is myosin II dependent, regardless of the therapy. ROCK-myosin II ablation specifically kills resistant cells via intrinsic lethal reactive oxygen species and unresolved DNA damage and limits extrinsic myeloid and lymphoid immunosuppression. Efficacy of targeted therapies and immunotherapies can be improved by combination with ROCK inhibitors.Graphical Graphical abstract for this article
       
  • Vitamin B6 Addiction in Acute Myeloid Leukemia
    • Abstract: Publication date: 13 January 2020Source: Cancer Cell, Volume 37, Issue 1Author(s): Chi-Chao Chen, Bo Li, Scott E. Millman, Cynthia Chen, Xiang Li, John P. Morris, Allison Mayle, Yu-Jui Ho, Evangelia Loizou, Hui Liu, Weige Qin, Hardik Shah, Sara Violante, Justin R. Cross, Scott W. Lowe, Lingbo ZhangSummaryCancer cells rely on altered metabolism to support abnormal proliferation. We performed a CRISPR/Cas9 functional genomic screen targeting metabolic enzymes and identified PDXK—an enzyme that produces pyridoxal phosphate (PLP) from vitamin B6—as an acute myeloid leukemia (AML)-selective dependency. PDXK kinase activity is required for PLP production and AML cell proliferation, and pharmacological blockade of the vitamin B6 pathway at both PDXK and PLP levels recapitulated PDXK disruption effects. PDXK disruption reduced intracellular concentrations of key metabolites needed for cell division. Furthermore, disruption of PLP-dependent enzymes ODC1 or GOT2 selectively inhibited AML cell proliferation and their downstream products partially rescued PDXK disruption induced proliferation blockage. Our work identifies the vitamin B6 pathway as a pharmacologically actionable dependency in AML.Graphical Graphical abstract for this article
       
  • Epigenetic Silencing of CDR1as Drives IGF2BP3-Mediated Melanoma
           Invasion and Metastasis
    • Abstract: Publication date: 13 January 2020Source: Cancer Cell, Volume 37, Issue 1Author(s): Douglas Hanniford, Alejandro Ulloa-Morales, Alcida Karz, Maria Gabriela Berzoti-Coelho, Rana S. Moubarak, Beatriz Sánchez-Sendra, Andreas Kloetgen, Veronica Davalos, Jochen Imig, Pamela Wu, Varshini Vasudevaraja, Diana Argibay, Karin Lilja, Tommaso Tabaglio, Carlos Monteagudo, Ernesto Guccione, Aristotelis Tsirigos, Iman Osman, Iannis Aifantis, Eva HernandoSummaryMetastasis is the primary cause of death of cancer patients. Dissecting mechanisms governing metastatic spread may uncover important tumor biology and/or yield promising therapeutic insights. Here, we investigated the role of circular RNAs (circRNA) in metastasis, using melanoma as a model aggressive tumor. We identified silencing of cerebellar degeneration-related 1 antisense (CDR1as), a regulator of miR-7, as a hallmark of melanoma progression. CDR1as depletion results from epigenetic silencing of LINC00632, its originating long non-coding RNA (lncRNA) and promotes invasion in vitro and metastasis in vivo through a miR-7-independent, IGF2BP3-mediated mechanism. Moreover, CDR1as levels reflect cellular states associated with distinct therapeutic responses. Our study reveals functional, prognostic, and predictive roles for CDR1as and expose circRNAs as key players in metastasis.Graphical Graphical abstract for this article
       
  • An Integrated Gene Expression Landscape Profiling Approach to Identify
           Lung Tumor Endothelial Cell Heterogeneity and Angiogenic Candidates
    • Abstract: Publication date: 13 January 2020Source: Cancer Cell, Volume 37, Issue 1Author(s): Jermaine Goveia, Katerina Rohlenova, Federico Taverna, Lucas Treps, Lena-Christin Conradi, Andreas Pircher, Vincent Geldhof, Laura P.M.H. de Rooij, Joanna Kalucka, Liliana Sokol, Melissa García-Caballero, Yingfeng Zheng, Junbin Qian, Laure-Anne Teuwen, Shawez Khan, Bram Boeckx, Els Wauters, Herbert Decaluwé, Paul De Leyn, Johan VansteenkisteSummaryHeterogeneity of lung tumor endothelial cell (TEC) phenotypes across patients, species (human/mouse), and models (in vivo/in vitro) remains poorly inventoried at the single-cell level. We single-cell RNA (scRNA)-sequenced 56,771 endothelial cells from human/mouse (peri)-tumoral lung and cultured human lung TECs, and detected 17 known and 16 previously unrecognized phenotypes, including TECs putatively regulating immune surveillance. We resolved the canonical tip TECs into a known migratory tip and a putative basement-membrane remodeling breach phenotype. Tip TEC signatures correlated with patient survival, and tip/breach TECs were most sensitive to vascular endothelial growth factor blockade. Only tip TECs were congruent across species/models and shared conserved markers. Integrated analysis of the scRNA-sequenced data with orthogonal multi-omics and meta-analysis data across different human tumors, validated by functional analysis, identified collagen modification as a candidate angiogenic pathway.Graphical Graphical abstract for this article
       
  • Cancer Genome Evolutionary Trajectories in Metastasis
    • Abstract: Publication date: 13 January 2020Source: Cancer Cell, Volume 37, Issue 1Author(s): Nicolai J. Birkbak, Nicholas McGranahanMetastatic cancer is a major cause of death and remains largely incurable. A better understanding of metastasis is therefore desperately needed to improve prognosis for late-stage disease. Here we survey the landscape of studies exploring the genomics of metastatic cancer. We consider evidence for genomic drivers of metastasis and explore studies investigating modes of metastatic spread.
       
  • Pangenomic Classification of Pituitary Neuroendocrine Tumors
    • Abstract: Publication date: Available online 26 December 2019Source: Cancer CellAuthor(s): Mario Neou, Chiara Villa, Roberta Armignacco, Anne Jouinot, Marie-Laure Raffin-Sanson, Amandine Septier, Franck Letourneur, Ségolène Diry, Marc Diedisheim, Brigitte Izac, Cassandra Gaspar, Karine Perlemoine, Victoria Verjus, Michèle Bernier, Anne Boulin, Jean-François Emile, Xavier Bertagna, Florence Jaffrezic, Denis Laloe, Bertrand BaussartSummaryPituitary neuroendocrine tumors (PitNETs) are common, with five main histological subtypes: lactotroph, somatotroph, and thyrotroph (POU1F1/PIT1 lineage); corticotroph (TBX19/TPIT lineage); and gonadotroph (NR5A1/SF1 lineage). We report a comprehensive pangenomic classification of PitNETs. PitNETs from POU1F1/PIT1 lineage showed an epigenetic signature of diffuse DNA hypomethylation, with transposable elements expression and chromosomal instability (except for GNAS-mutated somatotrophs). In TPIT lineage, corticotrophs were divided into three classes: the USP8-mutated with overt secretion, the USP8-wild-type with increased invasiveness and increased epithelial-mesenchymal transition, and the large silent tumors with gonadotroph transdifferentiation. Unexpected expression of gonadotroph markers was also found in GNAS-wild-type somatotrophs (SF1 expression), challenging the current definition of SF1/gonadotroph lineage. This classification improves our understanding and affects the clinical stratification of patients with PitNETs.Graphical Graphical abstract for this article
       
  • CDK7 Inhibition Potentiates Genome Instability Triggering Anti-tumor
           Immunity in Small Cell Lung Cancer
    • Abstract: Publication date: Available online 26 December 2019Source: Cancer CellAuthor(s): 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 HuangSummaryCyclin-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.Graphical Graphical abstract for this article
       
 
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