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1. Somatic rearrangements causing oncogenic ectodomain deletions of FGFR1 in squamous cell lung cancer

Author

Florian Malchers, Lucia Nogova, Martijn H.A. van Attekum, Lukas Maas, Johannes Brägelmann, Christoph Bartenhagen, Luc Girard, Graziella Bosco, Ilona Dahmen, Sebastian Michels, Clare E. Weeden, Andreas H. Scheel, Lydia Meder, Kristina Golfmann, Philipp Schuldt, Janna Siemanowski, Jan Rehker, Sabine Merkelbach-Bruse, Roopika Menon, Oliver Gautschi, Johannes M. Heuckmann, Elisabeth Brambilla, Marie-Liesse Asselin-Labat, Thorsten Persigehl, John D. Minna, Henning Walczak, Roland T. Ullrich, Matthias Fischer, Hans Christian Reinhardt, Jürgen Wolf, Reinhard Büttner, Martin Peifer, Julie George, and Roman K. Thomas

Subjects
Genetics, Oncology, Medicine
Abstract

The discovery of frequent 8p11-p12 amplifications in squamous cell lung cancer (SQLC) has fueled hopes that FGFR1, located inside this amplicon, might be a therapeutic target. In a clinical trial, only 11% of patients with 8p11 amplification (detected by FISH) responded to FGFR kinase inhibitor treatment. To understand the mechanism of FGFR1 dependency, we performed deep genomic characterization of 52 SQLCs with 8p11-p12 amplification, including 10 tumors obtained from patients who had been treated with FGFR inhibitors. We discovered somatically altered variants of FGFR1 with deletion of exons 1–8 that resulted from intragenic tail-to-tail rearrangements. These ectodomain-deficient FGFR1 variants (ΔEC-FGFR1) were expressed in the affected tumors and were tumorigenic in both in vitro and in vivo models of lung cancer. Mechanistically, breakage-fusion-bridges were the source of 8p11-p12 amplification, resulting from frequent head-to-head and tail-to-tail rearrangements. Generally, tail-to-tail rearrangements within or in close proximity upstream of FGFR1 were associated with FGFR1 dependency. Thus, the genomic events shaping the architecture of the 8p11-p12 amplicon provide a mechanistic explanation for the emergence of FGFR1-driven SQLC. Specifically, we believe that FGFR1 ectodomain–deficient and FGFR1-centered amplifications caused by tail-to-tail rearrangements are a novel somatic genomic event that might be predictive of therapeutically relevant FGFR1 dependency.

Published
2023
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2. Pulmonary cancers across different histotypes share hybrid tuft cell/ionocyte-like molecular features and potentially druggable vulnerabilities

Author

Yosuke Yamada, Djeda Belharazem-Vitacolonnna, Hanibal Bohnenberger, Christel Weiß, Naoko Matsui, Mark Kriegsmann, Katharina Kriegsmann, Peter Sinn, Katja Simon-Keller, Gerhard Hamilton, Thomas Graeter, Gerhard Preissler, German Ott, Sebastian Schölch, Naoki Nakajima, Akihiko Yoshizawa, Hironori Haga, Hiroshi Date, Roman K. Thomas, Iacopo Petrini, Giuseppe Giaccone, Philipp Ströbel, and Alexander Marx

Subjects
Cytology, QH573-671
Abstract

Abstract Tuft cells are chemosensory epithelial cells in the respiratory tract and several other organs. Recent studies revealed tuft cell-like gene expression signatures in some pulmonary adenocarcinomas, squamous cell carcinomas (SQCC), small cell carcinomas (SCLC), and large cell neuroendocrine carcinomas (LCNEC). Identification of their similarities could inform shared druggable vulnerabilities. Clinicopathological features of tuft cell-like (tcl) subsets in various lung cancer histotypes were studied in two independent tumor cohorts using immunohistochemistry (n = 674 and 70). Findings were confirmed, and additional characteristics were explored using public datasets (RNA seq and immunohistochemical data) (n = 555). Drug susceptibilities of tuft cell-like SCLC cell lines were also investigated. By immunohistochemistry, 10–20% of SCLC and LCNEC, and approximately 2% of SQCC expressed POU2F3, the master regulator of tuft cells. These tuft cell-like tumors exhibited “lineage ambiguity” as they co-expressed NCAM1, a marker for neuroendocrine differentiation, and KRT5, a marker for squamous differentiation. In addition, tuft cell-like tumors co-expressed BCL2 and KIT, and tuft cell-like SCLC and LCNEC, but not SQCC, also highly expressed MYC. Data from public datasets confirmed these features and revealed that tuft cell-like SCLC and LCNEC co-clustered on hierarchical clustering. Furthermore, only tuft cell-like subsets among pulmonary cancers significantly expressed FOXI1, the master regulator of ionocytes, suggesting their bidirectional but immature differentiation status. Clinically, tuft cell-like SCLC and LCNEC had a similar prognosis. Experimentally, tuft cell-like SCLC cell lines were susceptible to PARP and BCL2 co-inhibition, indicating synergistic effects. Taken together, pulmonary tuft cell-like cancers maintain histotype-related clinicopathologic characteristics despite overlapping unique molecular features. From a therapeutic perspective, identification of tuft cell-like LCNECs might be crucial given their close kinship with tuft cell-like SCLC.

Published
2022
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3. Clonal dynamics of BRAF-driven drug resistance in EGFR-mutant lung cancer

Author

Diana Schaufler, David F. Ast, Hannah L. Tumbrink, Nima Abedpour, Lukas Maas, Ayla E. Schwäbe, Inga Spille, Stefanie Lennartz, Jana Fassunke, Mihaela Aldea, Benjamin Besse, David Planchard, Lucia Nogova, Sebastian Michels, Carsten Kobe, Thorsten Persigehl, Theresa Westphal, Sophia Koleczko, Rieke Fischer, Jan-Phillip Weber, Janine Altmüller, Roman K. Thomas, Sabine Merkelbach-Bruse, Oliver Gautschi, Laura Mezquita, Reinhard Büttner, Jürgen Wolf, Martin Peifer, Johannes Brägelmann, Matthias Scheffler, and Martin L. Sos

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Activation of MAPK signaling via BRAF mutations may limit the activity of EGFR inhibitors in EGFR-mutant lung cancer patients. However, the impact of BRAF mutations on the selection and fitness of emerging resistant clones during anti-EGFR therapy remains elusive. We tracked the evolution of subclonal mutations by whole-exome sequencing and performed clonal analyses of individual metastases during therapy. Complementary functional analyses of polyclonal EGFR-mutant cell pools showed a dose-dependent enrichment of BRAF V600E and a loss of EGFR inhibitor susceptibility. The clones remain stable and become vulnerable to combined EGFR, RAF, and MEK inhibition. Moreover, only osimertinib/trametinib combination treatment, but not monotherapy with either of these drugs, leads to robust tumor shrinkage in EGFR-driven xenograft models harboring BRAF V600E mutations. These data provide insights into the dynamics of clonal evolution of EGFR-mutant tumors and the therapeutic implications of BRAF co-mutations that may facilitate the development of treatment strategies to improve the prognosis of these patients.

Published
2021
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4. Cold and heterogeneous T cell repertoire is associated with copy number aberrations and loss of immune genes in small-cell lung cancer

Author

Ming Chen, Runzhe Chen, Ying Jin, Jun Li, Xin Hu, Jiexin Zhang, Junya Fujimoto, Shawna M. Hubert, Carl M. Gay, Bo Zhu, Yanhua Tian, Nicholas McGranahan, Won-Chul Lee, Julie George, Xiao Hu, Yamei Chen, Meijuan Wu, Carmen Behrens, Chi-Wan Chow, Hoa H. N. Pham, Junya Fukuoka, Jia Wu, Edwin Roger Parra, Latasha D. Little, Curtis Gumbs, Xingzhi Song, Chang-Jiun Wu, Lixia Diao, Qi Wang, Robert Cardnell, Jianhua Zhang, Jing Wang, Xiuning Le, Don L. Gibbons, John V. Heymach, J. Jack Lee, William N. William, Chao Cheng, Bonnie Glisson, Ignacio Wistuba, P. Andrew Futreal, Roman K. Thomas, Alexandre Reuben, Lauren A. Byers, and Jianjun Zhang

Subjects
Science
Abstract

Small-cell lung cancer (SCLC) is an aggressive disease with limited therapeutic options. Here the authors perform an immunogenomic analysis of limited-stage SCLC, revealing a homogeneous mutational landscape, but limited T-cell infiltration and a cold and heterogeneous T cell repertoire.

Published
2021
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5. MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I

Author

Johannes Brägelmann, Carina Lorenz, Sven Borchmann, Kazuya Nishii, Julia Wegner, Lydia Meder, Jenny Ostendorp, David F. Ast, Alena Heimsoeth, Takamasa Nakasuka, Atsuko Hirabae, Sachi Okawa, Marcel A. Dammert, Dennis Plenker, Sebastian Klein, Philipp Lohneis, Jianing Gu, Laura K. Godfrey, Jan Forster, Marija Trajkovic-Arsic, Thomas Zillinger, Mareike Haarmann, Alexander Quaas, Stefanie Lennartz, Marcel Schmiel, Joshua D’Rozario, Emily S. Thomas, Henry Li, Clemens A. Schmitt, Julie George, Roman K. Thomas, Silvia von Karstedt, Gunther Hartmann, Reinhard Büttner, Roland T. Ullrich, Jens T. Siveke, Kadoaki Ohashi, Martin Schlee, and Martin L. Sos

Subjects
Science
Abstract

Kinase inhibitors are widely used to treat cancer, however patients frequently develop resistance. Here, the authors investigate adaption mechanisms during drug persistence and show that stimulation of the innate immunity sensor RIG-I enhances cancer cell death when combined with kinase inhibition.

Published
2021
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6. Ferroptosis response segregates small cell lung cancer (SCLC) neuroendocrine subtypes

Author

Christina M. Bebber, Emily S. Thomas, Jenny Stroh, Zhiyi Chen, Ariadne Androulidaki, Anna Schmitt, Michaela N. Höhne, Lukas Stüker, Cleidson de Pádua Alves, Armin Khonsari, Marcel A. Dammert, Fatma Parmaksiz, Hannah L. Tumbrink, Filippo Beleggia, Martin L. Sos, Jan Riemer, Julie George, Susanne Brodesser, Roman K. Thomas, H. Christian Reinhardt, and Silvia von Karstedt

Subjects
Science
Abstract

The high degree of subtype plasticity in small cell lung cancer (SCLC) poses a therapeutic challenge. Here, the authors show that the non-neuroendocrine (non-NE) subtype of SCLC is sensitive to ferroptosis while the neuroendocrine (NE) subtype is vulnerable to TRX anti-oxidant pathway inhibition, and the combination of these two treatments in SCLC circumvents non-NE/NE subtype plasticity.

Published
2021
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7. Texture analysis of iodine maps and conventional images for k-nearest neighbor classification of benign and metastatic lung nodules

Author

Simon Lennartz, Alina Mager, Nils Große Hokamp, Sebastian Schäfer, David Zopfs, David Maintz, Hans Christian Reinhardt, Roman K. Thomas, Liliana Caldeira, and Thorsten Persigehl

Subjects
Lung nodules, Staging, Diagnosis, Differentiation, Dual-energy CT, Spectral detector CT, Medical physics. Medical radiology. Nuclear medicine, R895-920, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background The purpose of this study was to analyze if the use of texture analysis on spectral detector CT (SDCT)-derived iodine maps (IM) in addition to conventional images (CI) improves lung nodule differentiation, when being applied to a k-nearest neighbor (KNN) classifier. Methods 183 cancer patients who underwent contrast-enhanced, venous phase SDCT of the chest were included: 85 patients with 146 benign lung nodules (BLN) confirmed by either prior/follow-up CT or histopathology and 98 patients with 425 lung metastases (LM) verified by histopathology, 18F-FDG-PET-CT or unequivocal change during treatment. Semi-automatic 3D segmentation of BLN/LM was performed, and volumetric HU attenuation and iodine concentration were acquired. For conventional images and iodine maps, average, standard deviation, entropy, kurtosis, mean of the positive pixels (MPP), skewness, uniformity and uniformity of the positive pixels (UPP) within the volumes of interests were calculated. All acquired parameters were transferred to a KNN classifier. Results Differentiation between BLN and LM was most accurate, when using all CI-derived features combined with the most significant IM-derived feature, entropy (Accuracy:0.87; F1/Dice:0.92). However, differentiation accuracy based on the 4 most powerful CI-derived features performed only slightly inferior (Accuracy:0.84; F1/Dice:0.89, p=0.125). Mono-parametric lung nodule differentiation based on either feature alone (i.e. attenuation or iodine concentration) was poor (AUC=0.65, 0.58, respectively). Conclusions First-order texture feature analysis of contrast-enhanced staging SDCT scans of the chest yield accurate differentiation between benign and metastatic lung nodules. In our study cohort, the most powerful iodine map-derived feature slightly, yet insignificantly increased classification accuracy compared to classification based on conventional image features only.

Published
2021
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8. Depletion of histone methyltransferase KMT9 inhibits lung cancer cell proliferation by inducing non-apoptotic cell death

Author

Hannah Maria Baumert, Eric Metzger, Matthias Fahrner, Julie George, Roman K. Thomas, Oliver Schilling, and Roland Schüle

Subjects
Lung cancer, Non-small cell lung cancer, A549, Epigenetics, Histone methyltransferase, KMT9, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Cytology, QH573-671
Abstract

Abstract Background Lung cancer is the leading cause of cancer related death worldwide. Over the past 15 years no major improvement of survival rates could be accomplished. The recently discovered histone methyltransferase KMT9 that acts as epigenetic regulator of prostate tumor growth has now raised hopes of enabling new cancer therapies. In this study, we aimed to identify the function of KMT9 in lung cancer. Methods We unraveled the KMT9 transcriptome and proteome in A549 lung adenocarcinoma cells using RNA-Seq and mass spectrometry and linked them with functional cell culture, real-time proliferation and flow cytometry assays. Results We show that KMT9α and -β subunits of KMT9 are expressed in lung cancer tissue and cell lines. Importantly, high levels of KMT9α correlate with poor patient survival. We identified 460 genes that are deregulated at the RNA and protein level upon knock-down of KMT9α in A549 cells. These genes cluster with proliferation, cell cycle and cell death gene sets as well as with subcellular organelles in gene ontology analysis. Knock-down of KMT9α inhibits lung cancer cell proliferation and induces non-apoptotic cell death in A549 cells. Conclusions The novel histone methyltransferase KMT9 is crucial for proliferation and survival of lung cancer cells harboring various mutations. Small molecule inhibitors targeting KMT9 therefore should be further examined as potential milestones in modern epigenetic lung cancer therapy.

Published
2020
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10. MYC paralog-dependent apoptotic priming orchestrates a spectrum of vulnerabilities in small cell lung cancer

Author

Marcel A. Dammert, Johannes Brägelmann, Rachelle R. Olsen, Stefanie Böhm, Niloufar Monhasery, Christopher P. Whitney, Milind D. Chalishazar, Hannah L. Tumbrink, Matthew R. Guthrie, Sebastian Klein, Abbie S. Ireland, Jeremy Ryan, Anna Schmitt, Annika Marx, Luka Ozretić, Roberta Castiglione, Carina Lorenz, Ron D. Jachimowicz, Elmar Wolf, Roman K. Thomas, John T. Poirier, Reinhard Büttner, Triparna Sen, Lauren A. Byers, H. Christian Reinhardt, Anthony Letai, Trudy G. Oliver, and Martin L. Sos

Subjects
Science
Abstract

The expression of oncogenic MYC paralogs in small cell lung cancer is mutually exclusive. In this study, the authors show that MYC, but not MYCN or MYCL, represses BCL2, resulting in cells that are uniquely sensitive to apoptosis, and find that CHK1 and AURKA inhibitors may be useful for treating these cancers.

Published
2019
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11. Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors

Author

Julie George, Vonn Walter, Martin Peifer, Ludmil B. Alexandrov, Danila Seidel, Frauke Leenders, Lukas Maas, Christian Müller, Ilona Dahmen, Tiffany M. Delhomme, Maude Ardin, Noemie Leblay, Graham Byrnes, Ruping Sun, Aurélien De Reynies, Anne McLeer-Florin, Graziella Bosco, Florian Malchers, Roopika Menon, Janine Altmüller, Christian Becker, Peter Nürnberg, Viktor Achter, Ulrich Lang, Peter M. Schneider, Magdalena Bogus, Matthew G. Soloway, Matthew D. Wilkerson, Yupeng Cun, James D. McKay, Denis Moro-Sibilot, Christian G. Brambilla, Sylvie Lantuejoul, Nicolas Lemaitre, Alex Soltermann, Walter Weder, Verena Tischler, Odd Terje Brustugun, Marius Lund-Iversen, Åslaug Helland, Steinar Solberg, Sascha Ansén, Gavin Wright, Benjamin Solomon, Luca Roz, Ugo Pastorino, Iver Petersen, Joachim H. Clement, Jörg Sänger, Jürgen Wolf, Martin Vingron, Thomas Zander, Sven Perner, William D. Travis, Stefan A. Haas, Magali Olivier, Matthieu Foll, Reinhard Büttner, David Neil Hayes, Elisabeth Brambilla, Lynnette Fernandez-Cuesta, and Roman K. Thomas

Subjects
Science
Abstract

The molecular nature of large-cell neuroendocrine lung carcinomas (LCNEC) has remained unclear. Here, the authors show LCNECs represent a distinct transcriptional subgroup among lung cancers and comprise two molecular subgroups, type I (TP53 and STK11/KEAP1 alterations) and type II (TP53 and RB1 inactivation).

Published
2018
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12. Systematic Kinase Inhibitor Profiling Identifies CDK9 as a Synthetic Lethal Target in NUT Midline Carcinoma

Author

Johannes Brägelmann, Marcel A. Dammert, Felix Dietlein, Johannes M. Heuckmann, Axel Choidas, Stefanie Böhm, André Richters, Debjit Basu, Verena Tischler, Carina Lorenz, Peter Habenberger, Zhizhou Fang, Sandra Ortiz-Cuaran, Frauke Leenders, Jan Eickhoff, Uwe Koch, Matthäus Getlik, Martin Termathe, Muhammad Sallouh, Zoltán Greff, Zoltán Varga, Hyatt Balke-Want, Christopher A. French, Martin Peifer, H. Christian Reinhardt, László Örfi, György Kéri, Sascha Ansén, Lukas C. Heukamp, Reinhard Büttner, Daniel Rauh, Bert M. Klebl, Roman K. Thomas, and Martin L. Sos

Subjects
high-throughput screen, NUT midline carcinoma, CDK9 inhibitor, transcriptional elongation, Biology (General), QH301-705.5
Abstract

Kinase inhibitors represent the backbone of targeted cancer therapy, yet only a limited number of oncogenic drivers are directly druggable. By interrogating the activity of 1,505 kinase inhibitors, we found that BRD4-NUT-rearranged NUT midline carcinoma (NMC) cells are specifically killed by CDK9 inhibition (CDK9i) and depend on CDK9 and Cyclin-T1 expression. We show that CDK9i leads to robust induction of apoptosis and of markers of DNA damage response in NMC cells. While both CDK9i and bromodomain inhibition over time result in reduced Myc protein expression, only bromodomain inhibition induces cell differentiation and a p21-induced cell-cycle arrest in these cells. Finally, RNA-seq and ChIP-based analyses reveal a BRD4-NUT-specific CDK9i-induced perturbation of transcriptional elongation. Thus, our data provide a mechanistic basis for the genotype-dependent vulnerability of NMC cells to CDK9i that may be of relevance for the development of targeted therapies for NMC patients.

Published
2017
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13. The tumour suppressor CYLD regulates the p53 DNA damage response

Author

Vanesa Fernández-Majada, Patrick-Simon Welz, Maria A. Ermolaeva, Michael Schell, Alexander Adam, Felix Dietlein, David Komander, Reinhard Büttner, Roman K. Thomas, Björn Schumacher, and Manolis Pasparakis

Subjects
Science
Abstract

CYLD is a deubiquitinase known to act as a tumour suppressor in different models of carcinogenesis. Here, the authors show that CYLD suppresses carcinogen-induced tumorigenesis by deubiquitinating p53 and promoting its stabilization and activation in response to DNA damage.

Published
2016
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14. Table S1 from Distinct Genetically Determined Origins of Myd88/BCL2-Driven Aggressive Lymphoma Rationalize Targeted Therapeutic Intervention Strategies

Author

Gero Knittel, Hans Christian Reinhardt, Ari M. Melnick, Ron D. Jachimowicz, Bastian von Tresckow, F. Thomas Wunderlich, Branko Zevnik, Bjoern Chapuy, Joachim R. Göthert, Sebastian Klein, Markus Chmielewski, Dinis Pedro Calado, Michael Hallek, Thorsten Persigehl, Monika Ortmann, Jörn Meinel, Philipp Lohneis, Reinhard Büttner, Alessandra Holzem, Filippo Beleggia, Lorenz Jonigkeit, Jacqueline Knüfer, Moritz Kochanek, Roman K. Thomas, Graziella Bosco, Nima Abedpour, Martin Peifer, Phuong-Hien Nguyen, Viktoria Kohlhas, Tobias Riet, Ilmars Kisis, Tim Lohmann, Pascal Nieper, Benedikt W. Pelzer, Julia Hansen, and Ruth Flümann

Abstract

Table S1 contains the p values of comparisons of the V gene usage in non-malignant GC B cells between the individual genotypes. These comparisons were done on the family, gene and allele level. V usage was compared for all BCR sequences as well as for isotype subsets.

Published
2023

15. Supplementary Figures S1 to S12 from Distinct Genetically Determined Origins of Myd88/BCL2-Driven Aggressive Lymphoma Rationalize Targeted Therapeutic Intervention Strategies

Author

Gero Knittel, Hans Christian Reinhardt, Ari M. Melnick, Ron D. Jachimowicz, Bastian von Tresckow, F. Thomas Wunderlich, Branko Zevnik, Bjoern Chapuy, Joachim R. Göthert, Sebastian Klein, Markus Chmielewski, Dinis Pedro Calado, Michael Hallek, Thorsten Persigehl, Monika Ortmann, Jörn Meinel, Philipp Lohneis, Reinhard Büttner, Alessandra Holzem, Filippo Beleggia, Lorenz Jonigkeit, Jacqueline Knüfer, Moritz Kochanek, Roman K. Thomas, Graziella Bosco, Nima Abedpour, Martin Peifer, Phuong-Hien Nguyen, Viktoria Kohlhas, Tobias Riet, Ilmars Kisis, Tim Lohmann, Pascal Nieper, Benedikt W. Pelzer, Julia Hansen, and Ruth Flümann

Abstract

This file contains the Supplementary Figures S1 to S12.

Published
2023

16. Data from Distinct Genetically Determined Origins of Myd88/BCL2-Driven Aggressive Lymphoma Rationalize Targeted Therapeutic Intervention Strategies

Author

Gero Knittel, Hans Christian Reinhardt, Ari M. Melnick, Ron D. Jachimowicz, Bastian von Tresckow, F. Thomas Wunderlich, Branko Zevnik, Bjoern Chapuy, Joachim R. Göthert, Sebastian Klein, Markus Chmielewski, Dinis Pedro Calado, Michael Hallek, Thorsten Persigehl, Monika Ortmann, Jörn Meinel, Philipp Lohneis, Reinhard Büttner, Alessandra Holzem, Filippo Beleggia, Lorenz Jonigkeit, Jacqueline Knüfer, Moritz Kochanek, Roman K. Thomas, Graziella Bosco, Nima Abedpour, Martin Peifer, Phuong-Hien Nguyen, Viktoria Kohlhas, Tobias Riet, Ilmars Kisis, Tim Lohmann, Pascal Nieper, Benedikt W. Pelzer, Julia Hansen, and Ruth Flümann

Abstract

Genomic profiling revealed the identity of at least 5 subtypes of diffuse large B-cell lymphoma (DLBCL), including the MCD/C5 cluster characterized by aberrations in MYD88, BCL2, PRDM1, and/or SPIB. We generated mouse models harboring B cell–specific Prdm1 or Spib aberrations on the background of oncogenic Myd88 and Bcl2 lesions. We deployed whole-exome sequencing, transcriptome, flow-cytometry, and mass cytometry analyses to demonstrate that Prdm1- or Spib-altered lymphomas display molecular features consistent with prememory B cells and light-zone B cells, whereas lymphomas lacking these alterations were enriched for late light-zone and plasmablast-associated gene sets. Consistent with the phenotypic evidence for increased B cell receptor signaling activity in Prdm1-altered lymphomas, we demonstrate that combined BTK/BCL2 inhibition displays therapeutic activity in mice and in five of six relapsed/refractory DLBCL patients. Moreover, Prdm1-altered lymphomas were immunogenic upon transplantation into immuno-competent hosts, displayed an actionable PD-L1 surface expression, and were sensitive to antimurine-CD19-CAR-T cell therapy, in vivo.Significance:Relapsed/refractory DLBCL remains a major medical challenge, and most of these patients succumb to their disease. Here, we generated mouse models, faithfully recapitulating the biology of MYD88-driven human DLBCL. These models revealed robust preclinical activity of combined BTK/BCL2 inhibition. We confirmed activity of this regimen in pretreated non–GCB-DLBCL patients.See related commentary by Leveille et al., p. 8.This article is highlighted in the In This Issue feature, p. 1

Published
2023

17. Supplementary Figure from CD74-NRG1 Fusions Are Oncogenic In Vivo and Induce Therapeutically Tractable ERBB2:ERBB3 Heterodimerization

Author

Roman K. Thomas, H. Christian Reinhardt, Martin L. Sos, Martin Peifer, Alison M. Schram, F. Thomas Wunderlich, Kevan M. Shokat, Thorsten Persigehl, Reinhard Büttner, Anna Schmitt, Sebastian Klein, Hannah L. Tumbrink, Johannes Brägelmann, Carina Lorenz, Marcel A. Dammert, Dennis Plenker, and Lisa Werr

Abstract

Supplementary Figure from CD74-NRG1 Fusions Are Oncogenic In Vivo and Induce Therapeutically Tractable ERBB2:ERBB3 Heterodimerization

Published
2023

18. Supplementary Tables S3-S8 from Genomic and Functional Fidelity of Small Cell Lung Cancer Patient-Derived Xenografts

Author

Anna F. Farago, Roman K. Thomas, Nicholas Dyson, Martin Peifer, Daniel A. Haber, Shyamala Maheswaran, Mehmet Toner, Aaron N. Hata, Kwok-Kin Wong, Alice T. Shaw, Lecia V. Sequist, Stefan Haas, Reinhard Büttner, Rebecca S. Heist, Sotirios Lakis, Roopika Menon, Nima Abedpour, Roxana Azimi, Kandarp N. Jani, Marina Kem, Maria Gomez-Caraballo, Joseph A. Licausi, Mehlika H. Hazar-Rethinam, Peter Igo, Jun Zhong, David T. Myers, Sarah Phat, Tilak Sundaresan, Ruben Dries, Mari Mino-Kenudson, Camilla L. Christensen, Julie George, and Benjamin J. Drapkin

Abstract

Supplementary Tables S3-S8

Published
2023

19. Interview with Dr. Meyerson from Mutations in the DDR2 Kinase Gene Identify a Novel Therapeutic Target in Squamous Cell Lung Cancer

Author

Matthew Meyerson, Roman K. Thomas, Eric B. Haura, Kwok-Kin Wong, Nathanael S. Gray, Daniel Rauh, Jeonghee Cho, Adam J. Bass, Heidi Greulich, Wendy Winckler, Bruce E. Johnson, Pasi A. Janne, Michael J. Eck, Charles Hatton, Megan Hanna, Ming Sound Tsao, David G. Beer, Jürgen Wolf, Erich Stoelben, Hannie Sietsma, Wim Timens, Harry Groen, Joachim H. Clement, Iver Petersen, Åslaug Helland, Odd Terje Brustugun, Philippe Lorimier, Christian Brambilla, Elisabeth Brambilla, Sascha Ansén, Silvia Querings, Franziska Gabler, Frauke Leenders, Mirjam Koker, Holger Moch, Alex Soltermann, Johannes M. Heuckmann, Thomas Zander, Danila Seidel, Helga B. Salvesen, Robert C. Onofrio, Michael S. Lawrence, Jeffrey R. Simard, Martin Peifer, Stefanie Heynck, Sang Min Lim, Xianming Deng, Jianming Zhang, Wenchu Lin, Brittany A. Woods, Lear E. Brace, Wenjun Zhou, Amit Dutt, Chunxiao Xu, Alex H. Ramos, Martin L. Sos, and Peter S. Hammerman

Abstract

mp3 file (6.8 MB). In the inaugural edition of the Cancer Discovery podcast, Executive Editor Mark Landis talks with Matthew Meyerson about his paper, which describes the identification of the DDR2 kinase as a therapeutic target in squamous cell lung cancer.

Published
2023

20. Supplementary Tables from CD74–NRG1 Fusions in Lung Adenocarcinoma

Author

Roman K. Thomas, Yasushi Yatabe, Stefan A. Haas, Sascha Ansén, Sven Perner, Jürgen Wolf, Thomas Zander, Reinhard Buettner, Lukas C. Heukamp, Martin Vingron, Dirk Brehmer, Marc Parade, Souichi Ogata, Timothy Perera, Idoya Lahortiga, Vito M. Fazio, Annamaria la Torre, Lucia A. Muscarella, Jörg Sänger, Joachim H. Clement, Iver Petersen, Erich Stoelben, Johannes M. Heuckmann, Peter Nürnberg, Christian Becker, Janine Altmüller, Sylvie Lantuejoul, Christian G. Brambilla, Denis Moro-Sibilot, Hélène Nagy-Mignotte, Elisabeth Brambilla, Benjamin Solomon, Zoe Wainer, Prudence A. Russell, Gavin M. Wright, Roland T. Ullrich, Mirjam Koker, Ilona Dahmen, Wenzel Vogel, Jakob Schöttle, Florian Malchers, Juliane Daßler, Marc Bos, Martin Peifer, Sandra Ortiz-Cuaran, Frauke Leenders, Roopika Menon, Ruping Sun, Hirotaka Osada, Dennis Plenker, and Lynnette Fernandez-Cuesta

Abstract

XLSX file 75K, This is an excel file containing 9 sheets, one for each of the 9 supplementary tables (S1 to S9) mentioned in the main text

Published
2023

21. Supplementary Table 1 from Mutations in the DDR2 Kinase Gene Identify a Novel Therapeutic Target in Squamous Cell Lung Cancer

Author

Matthew Meyerson, Roman K. Thomas, Eric B. Haura, Kwok-Kin Wong, Nathanael S. Gray, Daniel Rauh, Jeonghee Cho, Adam J. Bass, Heidi Greulich, Wendy Winckler, Bruce E. Johnson, Pasi A. Janne, Michael J. Eck, Charles Hatton, Megan Hanna, Ming Sound Tsao, David G. Beer, Jürgen Wolf, Erich Stoelben, Hannie Sietsma, Wim Timens, Harry Groen, Joachim H. Clement, Iver Petersen, Åslaug Helland, Odd Terje Brustugun, Philippe Lorimier, Christian Brambilla, Elisabeth Brambilla, Sascha Ansén, Silvia Querings, Franziska Gabler, Frauke Leenders, Mirjam Koker, Holger Moch, Alex Soltermann, Johannes M. Heuckmann, Thomas Zander, Danila Seidel, Helga B. Salvesen, Robert C. Onofrio, Michael S. Lawrence, Jeffrey R. Simard, Martin Peifer, Stefanie Heynck, Sang Min Lim, Xianming Deng, Jianming Zhang, Wenchu Lin, Brittany A. Woods, Lear E. Brace, Wenjun Zhou, Amit Dutt, Chunxiao Xu, Alex H. Ramos, Martin L. Sos, and Peter S. Hammerman

Abstract

Supplementary Table 1 from Mutations in the DDR2 Kinase Gene Identify a Novel Therapeutic Target in Squamous Cell Lung Cancer

Published
2023

22. Data from CD74-NRG1 Fusions Are Oncogenic In Vivo and Induce Therapeutically Tractable ERBB2:ERBB3 Heterodimerization

Author

Roman K. Thomas, H. Christian Reinhardt, Martin L. Sos, Martin Peifer, Alison M. Schram, F. Thomas Wunderlich, Kevan M. Shokat, Thorsten Persigehl, Reinhard Büttner, Anna Schmitt, Sebastian Klein, Hannah L. Tumbrink, Johannes Brägelmann, Carina Lorenz, Marcel A. Dammert, Dennis Plenker, and Lisa Werr

Abstract

NRG1 fusions are recurrent somatic genome alterations occurring across several tumor types, including invasive mucinous lung adenocarcinomas and pancreatic ductal adenocarcinomas and are potentially actionable genetic alterations in these cancers. We initially discovered CD74-NRG1 as the first NRG1 fusion in lung adenocarcinomas, and many additional fusion partners have since been identified. Here, we present the first CD74-NRG1 transgenic mouse model and provide evidence that ubiquitous expression of the CD74-NRG1 fusion protein in vivo leads to tumor development at high frequency. Furthermore, we show that ERBB2:ERBB3 heterodimerization is a mechanistic event in transformation by CD74-NRG1 binding physically to ERBB3 and that CD74-NRG1–expressing cells proliferate independent of supplemented NRG1 ligand. Thus, NRG1 gene fusions are recurrent driver oncogenes that cause oncogene dependency. Consistent with these findings, patients with NRG1 fusion-positive cancers respond to therapy targeting the ERBB2:ERBB3 receptors.

Published
2023

23. Supplementary Figures from CD74–NRG1 Fusions in Lung Adenocarcinoma

Author

Roman K. Thomas, Yasushi Yatabe, Stefan A. Haas, Sascha Ansén, Sven Perner, Jürgen Wolf, Thomas Zander, Reinhard Buettner, Lukas C. Heukamp, Martin Vingron, Dirk Brehmer, Marc Parade, Souichi Ogata, Timothy Perera, Idoya Lahortiga, Vito M. Fazio, Annamaria la Torre, Lucia A. Muscarella, Jörg Sänger, Joachim H. Clement, Iver Petersen, Erich Stoelben, Johannes M. Heuckmann, Peter Nürnberg, Christian Becker, Janine Altmüller, Sylvie Lantuejoul, Christian G. Brambilla, Denis Moro-Sibilot, Hélène Nagy-Mignotte, Elisabeth Brambilla, Benjamin Solomon, Zoe Wainer, Prudence A. Russell, Gavin M. Wright, Roland T. Ullrich, Mirjam Koker, Ilona Dahmen, Wenzel Vogel, Jakob Schöttle, Florian Malchers, Juliane Daßler, Marc Bos, Martin Peifer, Sandra Ortiz-Cuaran, Frauke Leenders, Roopika Menon, Ruping Sun, Hirotaka Osada, Dennis Plenker, and Lynnette Fernandez-Cuesta

Abstract

PDF file 234K, This is a file containing the list of supplementary tables, the list of supplementary figures, as well as the 7 supplementary figures (S1 to S7) and their correspondent legends, mentioned in the main text

Published
2023

24. Supplementary Methods and Legends from Cell-Autonomous and Non–Cell-Autonomous Mechanisms of Transformation by Amplified FGFR1 in Lung Cancer

Author

Roman K. Thomas, Jürgen Wolf, Lukas C. Heukamp, Reinhard Büttner, Francois Ringeisen, H. Christian Reinhardt, Roland T. Ullrich, Thomas Zander, Daniel Rauh, Steffi Silling, Julie George, Srivari Chandrasekhar, Nagaraju Karre, Prathama S. Mainkar, Alexandra Florin, Martin Peifer, André Richters, Frauke Leenders, Danila Seidel, Marc Bos, Matthias Scheffler, Masyar Gardizi, Dennis Plenker, Joachim Diebold, Oliver Gautschi, Johannes M. Heuckmann, Lynnette Fernandez-Cuesta, Kerstin Albus, Lucia Nogova, Xin Lu, Jakob Schöttle, Felix Dietlein, and Florian Malchers

Abstract

PDF file 136K,Methods: Additional information on experimental techniques and data analysis. Legends: describing supplementary figures S1-S14

Published
2023

25. Supplementary Figures S1-S14 from Cell-Autonomous and Non–Cell-Autonomous Mechanisms of Transformation by Amplified FGFR1 in Lung Cancer

Author

Roman K. Thomas, Jürgen Wolf, Lukas C. Heukamp, Reinhard Büttner, Francois Ringeisen, H. Christian Reinhardt, Roland T. Ullrich, Thomas Zander, Daniel Rauh, Steffi Silling, Julie George, Srivari Chandrasekhar, Nagaraju Karre, Prathama S. Mainkar, Alexandra Florin, Martin Peifer, André Richters, Frauke Leenders, Danila Seidel, Marc Bos, Matthias Scheffler, Masyar Gardizi, Dennis Plenker, Joachim Diebold, Oliver Gautschi, Johannes M. Heuckmann, Lynnette Fernandez-Cuesta, Kerstin Albus, Lucia Nogova, Xin Lu, Jakob Schöttle, Felix Dietlein, and Florian Malchers

Abstract

PDF file 34156K, Table of genes from 16 recurrent amplified genomic regions (Figure S1), amplicon focality on TCGA copy number aberrations (Figure S2), hierarchical clustering of CLCGP copy number data (Figure S3), centrality frequencies of common cancer genes (Figure S4), genotypic cell line annotation (Figure S5), receptor signaling activation of H520 and HCC15 lines (Figure S6), experimental draft for ligand dependency (Figure S7), whole transcriptome analysis FGFR1 splicing (Figure S8), validation of gene expression by qPCR (Figure S9), tumor formation of FGFR1α cells in nude mice (Figure S10), quantification of MYC stains in murine tumor samples (Figure S11), apoptosis is accompanied by cytochrome c release and breakdown of mitochondrial potential (Figure S12), IHC scores of FGFR phosphorylation and MYC expression (Figure S13), High MYC expression identifies a second responder to FGFR inhibitory therapy (Figure S14)

Published
2023

26. Supplementary Figures 1-7 from Mutations in the DDR2 Kinase Gene Identify a Novel Therapeutic Target in Squamous Cell Lung Cancer

Author

Matthew Meyerson, Roman K. Thomas, Eric B. Haura, Kwok-Kin Wong, Nathanael S. Gray, Daniel Rauh, Jeonghee Cho, Adam J. Bass, Heidi Greulich, Wendy Winckler, Bruce E. Johnson, Pasi A. Janne, Michael J. Eck, Charles Hatton, Megan Hanna, Ming Sound Tsao, David G. Beer, Jürgen Wolf, Erich Stoelben, Hannie Sietsma, Wim Timens, Harry Groen, Joachim H. Clement, Iver Petersen, Åslaug Helland, Odd Terje Brustugun, Philippe Lorimier, Christian Brambilla, Elisabeth Brambilla, Sascha Ansén, Silvia Querings, Franziska Gabler, Frauke Leenders, Mirjam Koker, Holger Moch, Alex Soltermann, Johannes M. Heuckmann, Thomas Zander, Danila Seidel, Helga B. Salvesen, Robert C. Onofrio, Michael S. Lawrence, Jeffrey R. Simard, Martin Peifer, Stefanie Heynck, Sang Min Lim, Xianming Deng, Jianming Zhang, Wenchu Lin, Brittany A. Woods, Lear E. Brace, Wenjun Zhou, Amit Dutt, Chunxiao Xu, Alex H. Ramos, Martin L. Sos, and Peter S. Hammerman

Abstract

Supplementary Figures 1-7 from Mutations in the DDR2 Kinase Gene Identify a Novel Therapeutic Target in Squamous Cell Lung Cancer

Published
2023

27. Supplementary Figures 1-11 from Genomic and Functional Fidelity of Small Cell Lung Cancer Patient-Derived Xenografts

Author

Anna F. Farago, Roman K. Thomas, Nicholas Dyson, Martin Peifer, Daniel A. Haber, Shyamala Maheswaran, Mehmet Toner, Aaron N. Hata, Kwok-Kin Wong, Alice T. Shaw, Lecia V. Sequist, Stefan Haas, Reinhard Büttner, Rebecca S. Heist, Sotirios Lakis, Roopika Menon, Nima Abedpour, Roxana Azimi, Kandarp N. Jani, Marina Kem, Maria Gomez-Caraballo, Joseph A. Licausi, Mehlika H. Hazar-Rethinam, Peter Igo, Jun Zhong, David T. Myers, Sarah Phat, Tilak Sundaresan, Ruben Dries, Mari Mino-Kenudson, Camilla L. Christensen, Julie George, and Benjamin J. Drapkin

Abstract

Supplementary Figures 1-11

Published
2023

28. Data from CD74–NRG1 Fusions in Lung Adenocarcinoma

Author

Roman K. Thomas, Yasushi Yatabe, Stefan A. Haas, Sascha Ansén, Sven Perner, Jürgen Wolf, Thomas Zander, Reinhard Buettner, Lukas C. Heukamp, Martin Vingron, Dirk Brehmer, Marc Parade, Souichi Ogata, Timothy Perera, Idoya Lahortiga, Vito M. Fazio, Annamaria la Torre, Lucia A. Muscarella, Jörg Sänger, Joachim H. Clement, Iver Petersen, Erich Stoelben, Johannes M. Heuckmann, Peter Nürnberg, Christian Becker, Janine Altmüller, Sylvie Lantuejoul, Christian G. Brambilla, Denis Moro-Sibilot, Hélène Nagy-Mignotte, Elisabeth Brambilla, Benjamin Solomon, Zoe Wainer, Prudence A. Russell, Gavin M. Wright, Roland T. Ullrich, Mirjam Koker, Ilona Dahmen, Wenzel Vogel, Jakob Schöttle, Florian Malchers, Juliane Daßler, Marc Bos, Martin Peifer, Sandra Ortiz-Cuaran, Frauke Leenders, Roopika Menon, Ruping Sun, Hirotaka Osada, Dennis Plenker, and Lynnette Fernandez-Cuesta

Abstract

We discovered a novel somatic gene fusion, CD74–NRG1, by transcriptome sequencing of 25 lung adenocarcinomas of never smokers. By screening 102 lung adenocarcinomas negative for known oncogenic alterations, we found four additional fusion-positive tumors, all of which were of the invasive mucinous subtype. Mechanistically, CD74–NRG1 leads to extracellular expression of the EGF-like domain of NRG1 III-β3, thereby providing the ligand for ERBB2–ERBB3 receptor complexes. Accordingly, ERBB2 and ERBB3 expression was high in the index case, and expression of phospho-ERBB3 was specifically found in tumors bearing the fusion (P < 0.0001). Ectopic expression of CD74–NRG1 in lung cancer cell lines expressing ERBB2 and ERBB3 activated ERBB3 and the PI3K–AKT pathway, and led to increased colony formation in soft agar. Thus, CD74–NRG1 gene fusions are activating genomic alterations in invasive mucinous adenocarcinomas and may offer a therapeutic opportunity for a lung tumor subtype with, so far, no effective treatment.Significance: CD74–NRG1 fusions may represent a therapeutic opportunity for invasive mucinous lung adenocarcinomas, a tumor with no effective treatment that frequently presents with multifocal unresectable disease. Cancer Discov; 4(4); 415–22. ©2014 AACR.This article is highlighted in the In This Issue feature, p. 377

Published
2023

29. Supplementary Figure Legends 1-7 from Mutations in the DDR2 Kinase Gene Identify a Novel Therapeutic Target in Squamous Cell Lung Cancer

Author

Matthew Meyerson, Roman K. Thomas, Eric B. Haura, Kwok-Kin Wong, Nathanael S. Gray, Daniel Rauh, Jeonghee Cho, Adam J. Bass, Heidi Greulich, Wendy Winckler, Bruce E. Johnson, Pasi A. Janne, Michael J. Eck, Charles Hatton, Megan Hanna, Ming Sound Tsao, David G. Beer, Jürgen Wolf, Erich Stoelben, Hannie Sietsma, Wim Timens, Harry Groen, Joachim H. Clement, Iver Petersen, Åslaug Helland, Odd Terje Brustugun, Philippe Lorimier, Christian Brambilla, Elisabeth Brambilla, Sascha Ansén, Silvia Querings, Franziska Gabler, Frauke Leenders, Mirjam Koker, Holger Moch, Alex Soltermann, Johannes M. Heuckmann, Thomas Zander, Danila Seidel, Helga B. Salvesen, Robert C. Onofrio, Michael S. Lawrence, Jeffrey R. Simard, Martin Peifer, Stefanie Heynck, Sang Min Lim, Xianming Deng, Jianming Zhang, Wenchu Lin, Brittany A. Woods, Lear E. Brace, Wenjun Zhou, Amit Dutt, Chunxiao Xu, Alex H. Ramos, Martin L. Sos, and Peter S. Hammerman

Abstract

Supplementary Figure Legends 1-7 from Mutations in the DDR2 Kinase Gene Identify a Novel Therapeutic Target in Squamous Cell Lung Cancer

Published
2023

30. Supplementary text from Genomic and Functional Fidelity of Small Cell Lung Cancer Patient-Derived Xenografts

Author

Anna F. Farago, Roman K. Thomas, Nicholas Dyson, Martin Peifer, Daniel A. Haber, Shyamala Maheswaran, Mehmet Toner, Aaron N. Hata, Kwok-Kin Wong, Alice T. Shaw, Lecia V. Sequist, Stefan Haas, Reinhard Büttner, Rebecca S. Heist, Sotirios Lakis, Roopika Menon, Nima Abedpour, Roxana Azimi, Kandarp N. Jani, Marina Kem, Maria Gomez-Caraballo, Joseph A. Licausi, Mehlika H. Hazar-Rethinam, Peter Igo, Jun Zhong, David T. Myers, Sarah Phat, Tilak Sundaresan, Ruben Dries, Mari Mino-Kenudson, Camilla L. Christensen, Julie George, and Benjamin J. Drapkin

Abstract

Text for supplement: Supplementary methods, supplementary figure legends

Published
2023

32. Supplementary Data from Blood-Based Gene Expression Signatures in Non–Small Cell Lung Cancer

Author

Jürgen Wolf, Joachim L. Schultze, Erich Stoelben, H.-Erich Wichmann, Walburga Engel-Riedel, Karl-Stefan Delank, Cornelia Mauch, Birgit Gathof, Roman K. Thomas, Marc Beyer, Moritz Hahn, Sascha Ansén, Daniela Maisel, Svenja Debey-Pascher, Sabine Classen, Andrea Staratschek-Jox, Andrea Hofmann, and Thomas Zander

Abstract

Supplementary Materials and Methods; Supplementary Tables S1-S3.

Published
2023

33. Supplementary Figures 1-5 from Mechanisms of Primary Drug Resistance in FGFR1-Amplified Lung Cancer

Author

Roman K. Thomas, Reinhard Büttner, Jürgen Wolf, Martin Peifer, Alex Soltermann, Martin L. Sos, Sascha Ansén, Julie George, Johannes M. Heuckmann, Roopika Menon, Johannes Brägelmann, Ilona Dahmen, Sebastian Michels, Verena Tischler, Roberta Castiglione, Daniel Schütte, Meryem Ercanoglu, and Florian Malchers

Abstract

Supplementary Figure 1 Short Tandem Repeat Analysis for H1581 and DMS114 Cells; Supplementary Figure 2 Genomic Alteration Validation of NRAS and DUSP6; Supplementary Figure 3 Genomic Differences in DMS114 and DMS114_BGJp Cells; Supplementary Figure 4 Transcriptional Change of DMS114 and DMS114_BGJr; Supplementary Figure 5 Analysis of a Patient with a Relapse under BGJ398

Published
2023

34. Supplementary Fig S5 from Genomic Amplification of CD274 (PD-L1) in Small-Cell Lung Cancer

Author

Takashi Kohno, Roman K. Thomas, Jun Yokota, Curtis C. Harris, Reinhard Büttner, Iver Petersen, Se Jin Jang, Martin Peifer, Masayuki Noguchi, Ryo Nishikawa, Shun-ichi Watanabe, Shinsuke Uchida, Andreas H. Scheel, Kouya Shiraishi, Reika Iwakawa, Koji Tsuta, Motonobu Saito, and Julie George

Abstract

Analysis of immune cell signatures

Published
2023

35. Supplementary Figure 4 from Heterogeneous Mechanisms of Primary and Acquired Resistance to Third-Generation EGFR Inhibitors

Author

Martin L. Sos, Roman K. Thomas, Jürgen Wolf, Reinhard Buettner, Martin Peifer, William Pao, Johannes Berg, Lukas C. Heukamp, Sascha Ansén, Peter Nuernberg, Johannes M. Heuckmann, Alexandra Florin, Christian Müller, Hongbin Ji, Janine Altmüller, Christian Becker, Carina Heydt, Helen Pasternack, Michaela A. Ihle, Jana Fassunke, Hans-Ulrich Schildhaus, Katharina König, Kerstin Albus, Rieke Fischer, Sebastian Michels, Marc Bos, Sabine Merkelbach-Bruse, Thorsten Persigehl, Christine M. Lovly, Lydia Meder, Lynnette Fernandez-Cuesta, Andreas H. Scheel, llona Dahmen, Dennis Plenker, Matthias Scheffler, and Sandra Ortiz-Cuaran

Abstract

Concomitant inhibition of MEK and EGFR is synergistic in PC9KRAS-G12S and HCC827KRAS-G12S cells.

Published
2023

36. Supplementary Figure 2 from Translating the Therapeutic Potential of AZD4547 in FGFR1-Amplified Non–Small Cell Lung Cancer through the Use of Patient-Derived Tumor Xenograft Models

Author

Paul R. Gavine, Roman K. Thomas, A. Nigel Brooks, Paul D. Smith, Elaine Kilgour, Qunsheng Ji, Ping Zhan, Lili Tang, Ziliang Qian, Guanshan Zhu, Zhengwei Dong, Kunji Liu, YanPing Xu, XiaoLu Yin, ShuQiong Fan, Florian Malchers, Liang Xie, Ming Li, Xinying Su, Lin Zhang, and Jingchuan Zhang

Abstract

PDF file - 106K, Detection of FGFR1 gene amplification in DMS114 cells using FISH analysis

Published
2023

40. Supplementary Tables 1 - 4 from Translating the Therapeutic Potential of AZD4547 in FGFR1-Amplified Non–Small Cell Lung Cancer through the Use of Patient-Derived Tumor Xenograft Models

Author

Paul R. Gavine, Roman K. Thomas, A. Nigel Brooks, Paul D. Smith, Elaine Kilgour, Qunsheng Ji, Ping Zhan, Lili Tang, Ziliang Qian, Guanshan Zhu, Zhengwei Dong, Kunji Liu, YanPing Xu, XiaoLu Yin, ShuQiong Fan, Florian Malchers, Liang Xie, Ming Li, Xinying Su, Lin Zhang, and Jingchuan Zhang

Abstract

PDF file - 94K, Supplementary Table 1. AZD4547 GI50 comparisons between FGFR1-amplified DMS114 and EGFR-mutant NCI-H1975 cell lines. Supplementary Table 2. Dynamic modulation of pERK, pS6, Ki67 and CC3 markers in model L121 tumor sections treated with a single dose of 12.5mg/kg AZD4547. Supplementary Table 3. Statistical association analysis of tumor histology and patient smoking status. Supplementary Table 4. FGFR1 amplification shows high mutual exclusivity with EGFR, Kras and EML4-ALK status in Chinese NSCLC.

Published
2023

41. Supplementary Figure Legend from Translating the Therapeutic Potential of AZD4547 in FGFR1-Amplified Non–Small Cell Lung Cancer through the Use of Patient-Derived Tumor Xenograft Models

Author

Paul R. Gavine, Roman K. Thomas, A. Nigel Brooks, Paul D. Smith, Elaine Kilgour, Qunsheng Ji, Ping Zhan, Lili Tang, Ziliang Qian, Guanshan Zhu, Zhengwei Dong, Kunji Liu, YanPing Xu, XiaoLu Yin, ShuQiong Fan, Florian Malchers, Liang Xie, Ming Li, Xinying Su, Lin Zhang, and Jingchuan Zhang

Abstract

PDF file - 64K

Published
2023

42. Supplementary Table S4 from Genomic Amplification of CD274 (PD-L1) in Small-Cell Lung Cancer

Author

Takashi Kohno, Roman K. Thomas, Jun Yokota, Curtis C. Harris, Reinhard Büttner, Iver Petersen, Se Jin Jang, Martin Peifer, Masayuki Noguchi, Ryo Nishikawa, Shun-ichi Watanabe, Shinsuke Uchida, Andreas H. Scheel, Kouya Shiraishi, Reika Iwakawa, Koji Tsuta, Motonobu Saito, and Julie George

Abstract

Clinicopathological factors in 4 cases with PD-L1 focal amplification

Published
2023

43. Supplementary Data from Heterogeneous Mechanisms of Primary and Acquired Resistance to Third-Generation EGFR Inhibitors

Author

Martin L. Sos, Roman K. Thomas, Jürgen Wolf, Reinhard Buettner, Martin Peifer, William Pao, Johannes Berg, Lukas C. Heukamp, Sascha Ansén, Peter Nuernberg, Johannes M. Heuckmann, Alexandra Florin, Christian Müller, Hongbin Ji, Janine Altmüller, Christian Becker, Carina Heydt, Helen Pasternack, Michaela A. Ihle, Jana Fassunke, Hans-Ulrich Schildhaus, Katharina König, Kerstin Albus, Rieke Fischer, Sebastian Michels, Marc Bos, Sabine Merkelbach-Bruse, Thorsten Persigehl, Christine M. Lovly, Lydia Meder, Lynnette Fernandez-Cuesta, Andreas H. Scheel, llona Dahmen, Dennis Plenker, Matthias Scheffler, and Sandra Ortiz-Cuaran

Abstract

Supplementary figure legends

Published
2023

44. Supplementary Figure 1 from Heterogeneous Mechanisms of Primary and Acquired Resistance to Third-Generation EGFR Inhibitors

Author

Martin L. Sos, Roman K. Thomas, Jürgen Wolf, Reinhard Buettner, Martin Peifer, William Pao, Johannes Berg, Lukas C. Heukamp, Sascha Ansén, Peter Nuernberg, Johannes M. Heuckmann, Alexandra Florin, Christian Müller, Hongbin Ji, Janine Altmüller, Christian Becker, Carina Heydt, Helen Pasternack, Michaela A. Ihle, Jana Fassunke, Hans-Ulrich Schildhaus, Katharina König, Kerstin Albus, Rieke Fischer, Sebastian Michels, Marc Bos, Sabine Merkelbach-Bruse, Thorsten Persigehl, Christine M. Lovly, Lydia Meder, Lynnette Fernandez-Cuesta, Andreas H. Scheel, llona Dahmen, Dennis Plenker, Matthias Scheffler, and Sandra Ortiz-Cuaran

Abstract

Activation of ERBB2 or MET leads to decreased sensitivity to AZD9291 and rociletinib.

Published
2023

45. Data from Heterogeneous Mechanisms of Primary and Acquired Resistance to Third-Generation EGFR Inhibitors

Author

Martin L. Sos, Roman K. Thomas, Jürgen Wolf, Reinhard Buettner, Martin Peifer, William Pao, Johannes Berg, Lukas C. Heukamp, Sascha Ansén, Peter Nuernberg, Johannes M. Heuckmann, Alexandra Florin, Christian Müller, Hongbin Ji, Janine Altmüller, Christian Becker, Carina Heydt, Helen Pasternack, Michaela A. Ihle, Jana Fassunke, Hans-Ulrich Schildhaus, Katharina König, Kerstin Albus, Rieke Fischer, Sebastian Michels, Marc Bos, Sabine Merkelbach-Bruse, Thorsten Persigehl, Christine M. Lovly, Lydia Meder, Lynnette Fernandez-Cuesta, Andreas H. Scheel, llona Dahmen, Dennis Plenker, Matthias Scheffler, and Sandra Ortiz-Cuaran

Abstract

Purpose: To identify novel mechanisms of resistance to third-generation EGFR inhibitors in patients with lung adenocarcinoma that progressed under therapy with either AZD9291 or rociletinib (CO-1686).Experimental Design: We analyzed tumor biopsies from seven patients obtained before, during, and/or after treatment with AZD9291 or rociletinib (CO-1686). Targeted sequencing and FISH analyses were performed, and the relevance of candidate genes was functionally assessed in in vitro models.Results: We found recurrent amplification of either MET or ERBB2 in tumors that were resistant or developed resistance to third-generation EGFR inhibitors and show that ERBB2 and MET activation can confer resistance to these compounds. Furthermore, we identified a KRASG12S mutation in a patient with acquired resistance to AZD9291 as a potential driver of acquired resistance. Finally, we show that dual inhibition of EGFR/MEK might be a viable strategy to overcome resistance in EGFR-mutant cells expressing mutant KRAS.Conclusions: Our data suggest that heterogeneous mechanisms of resistance can drive primary and acquired resistance to third-generation EGFR inhibitors and provide a rationale for potential combination strategies. Clin Cancer Res; 22(19); 4837–47. ©2016 AACR.

Published
2023

46. Supplementary Figure 1 from Translating the Therapeutic Potential of AZD4547 in FGFR1-Amplified Non–Small Cell Lung Cancer through the Use of Patient-Derived Tumor Xenograft Models

Author

Paul R. Gavine, Roman K. Thomas, A. Nigel Brooks, Paul D. Smith, Elaine Kilgour, Qunsheng Ji, Ping Zhan, Lili Tang, Ziliang Qian, Guanshan Zhu, Zhengwei Dong, Kunji Liu, YanPing Xu, XiaoLu Yin, ShuQiong Fan, Florian Malchers, Liang Xie, Ming Li, Xinying Su, Lin Zhang, and Jingchuan Zhang

Abstract

PDF file - 219K, AZD4547 demonstrates potent anti-tumor efficacy in the standard FGFR1-amplified xenograft lung model, NCI-H1581

Published
2023

47. Supplementary Figure 2 from Heterogeneous Mechanisms of Primary and Acquired Resistance to Third-Generation EGFR Inhibitors

Author

Martin L. Sos, Roman K. Thomas, Jürgen Wolf, Reinhard Buettner, Martin Peifer, William Pao, Johannes Berg, Lukas C. Heukamp, Sascha Ansén, Peter Nuernberg, Johannes M. Heuckmann, Alexandra Florin, Christian Müller, Hongbin Ji, Janine Altmüller, Christian Becker, Carina Heydt, Helen Pasternack, Michaela A. Ihle, Jana Fassunke, Hans-Ulrich Schildhaus, Katharina König, Kerstin Albus, Rieke Fischer, Sebastian Michels, Marc Bos, Sabine Merkelbach-Bruse, Thorsten Persigehl, Christine M. Lovly, Lydia Meder, Lynnette Fernandez-Cuesta, Andreas H. Scheel, llona Dahmen, Dennis Plenker, Matthias Scheffler, and Sandra Ortiz-Cuaran

Abstract

Targeted and Sanger sequencing results at the EGFR locus for P6 and P7.

Published
2023

48. Supplementary Figure 3 from Heterogeneous Mechanisms of Primary and Acquired Resistance to Third-Generation EGFR Inhibitors

Author

Martin L. Sos, Roman K. Thomas, Jürgen Wolf, Reinhard Buettner, Martin Peifer, William Pao, Johannes Berg, Lukas C. Heukamp, Sascha Ansén, Peter Nuernberg, Johannes M. Heuckmann, Alexandra Florin, Christian Müller, Hongbin Ji, Janine Altmüller, Christian Becker, Carina Heydt, Helen Pasternack, Michaela A. Ihle, Jana Fassunke, Hans-Ulrich Schildhaus, Katharina König, Kerstin Albus, Rieke Fischer, Sebastian Michels, Marc Bos, Sabine Merkelbach-Bruse, Thorsten Persigehl, Christine M. Lovly, Lydia Meder, Lynnette Fernandez-Cuesta, Andreas H. Scheel, llona Dahmen, Dennis Plenker, Matthias Scheffler, and Sandra Ortiz-Cuaran

Abstract

Expression of KRASG12S mutant results in decreased sensitivity to AZD9291 and rociletinib in EGFR mutated cells.

Published
2023

49. Data from ALK Mutations Conferring Differential Resistance to Structurally Diverse ALK Inhibitors

Author

Roman K. Thomas, William Pao, Daniel Rauh, Christian Grütter, Christine M. Lovly, Jonathan Weiss, Martin Peifer, Mirjam Koker, Hyatt Balke-Want, Stefanie Heynck, Martin L. Sos, Michael Hölzel, and Johannes M. Heuckmann

Abstract

Purpose:EML4–ALK fusions define a subset of lung cancers that can be effectively treated with anaplastic lymphoma kinase (ALK) inhibitors. Unfortunately, the duration of response is heterogeneous and acquired resistance limits their ultimate efficacy. Thus, a better understanding of resistance mechanisms will help to enhance tumor control in EML4–ALK-positive tumors.Experimental Design: By applying orthogonal functional mutagenesis screening approaches, we screened for mutations inducing resistance to the aminopyridine PF02341066 (crizotinib) and/or the diaminopyrimidine TAE684.Results: Here, we show that the resistance mutation, L1196M, as well as other crizotinib resistance mutations (F1174L and G1269S), are highly sensitive to the structurally unrelated ALK inhibitor TAE684. In addition, we identified two novel EML4–ALK resistance mutations (L1198P and D1203N), which unlike previously reported mutations, induced resistance to both ALK inhibitors. An independent resistance screen in ALK-mutant neuroblastoma cells yielded the same L1198P resistance mutation but defined two additional mutations conferring resistance to TAE684 but not to PF02341066.Conclusions: Our results show that different ALK resistance mutations as well as different ALK inhibitors impact the therapeutic efficacy in the setting of EML4–ALK fusions and ALK mutations. Clin Cancer Res; 17(23); 7394–401. ©2011 AACR.

Published
2023

50. Data from Mechanisms of Primary Drug Resistance in FGFR1-Amplified Lung Cancer

Author

Roman K. Thomas, Reinhard Büttner, Jürgen Wolf, Martin Peifer, Alex Soltermann, Martin L. Sos, Sascha Ansén, Julie George, Johannes M. Heuckmann, Roopika Menon, Johannes Brägelmann, Ilona Dahmen, Sebastian Michels, Verena Tischler, Roberta Castiglione, Daniel Schütte, Meryem Ercanoglu, and Florian Malchers

Abstract

Purpose: The 8p12-p11 locus is frequently amplified in squamous cell lung cancer (SQLC); the receptor tyrosine kinase fibroblast growth factor receptor 1 (FGFR1) being one of the most prominent targets of this amplification. Thus, small molecules inhibiting FGFRs have been employed to treat FGFR1-amplified SQLC. However, only about 11% of such FGFR1-amplified tumors respond to single-agent FGFR inhibition and several tumors exhibited insufficient tumor shrinkage, compatible with the existence of drug-resistant tumor cells.Experimental Design: To investigate possible mechanisms of resistance to FGFR inhibition, we studied the lung cancer cell lines DMS114 and H1581. Both cell lines are highly sensitive to three different FGFR inhibitors, but exhibit sustained residual cellular viability under treatment, indicating a subpopulation of existing drug-resistant cells. We isolated these subpopulations by treating the cells with constant high doses of FGFR inhibitors.Results: The FGFR inhibitor–resistant cells were cross-resistant and characterized by sustained MAPK pathway activation. In drug-resistant H1581 cells, we identified NRAS amplification and DUSP6 deletion, leading to MAPK pathway reactivation. Furthermore, we detected subclonal NRAS amplifications in 3 of 20 (15%) primary human FGFR1-amplified SQLC specimens. In contrast, drug-resistant DMS114 cells exhibited transcriptional upregulation of MET that drove MAPK pathway reactivation. As a consequence, we demonstrate that rational combination therapies resensitize resistant cells to treatment with FGFR inhibitors.Conclusions: We provide evidence for the existence of diverse mechanisms of primary drug resistance in FGFR1-amplified lung cancer and provide a rational strategy to improve FGFR inhibitor therapies by combination treatment. Clin Cancer Res; 23(18); 5527–36. ©2017 AACR.

Published
2023

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