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1. Direct and selective pharmacological disruption of the YAP–TEAD interface by IAG933 inhibits Hippo-dependent and RAS–MAPK-altered cancers

Author

Chapeau, Emilie A., Sansregret, Laurent, Galli, Giorgio G., Chène, Patrick, Wartmann, Markus, Mourikis, Thanos P., Jaaks, Patricia, Baltschukat, Sabrina, Barbosa, Ines A. M., Bauer, Daniel, Brachmann, Saskia M., Delaunay, Clara, Estadieu, Claire, Faris, Jason E., Furet, Pascal, Harlfinger, Stefanie, Hueber, Andreas, Jiménez Núñez, Eloísa, Kodack, David P., Mandon, Emeline, Martin, Typhaine, Mesrouze, Yannick, Romanet, Vincent, Scheufler, Clemens, Sellner, Holger, Stamm, Christelle, Sterker, Dario, Tordella, Luca, Hofmann, Francesco, Soldermann, Nicolas, and Schmelzle, Tobias

Published
2024
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2. Discovery of WRN inhibitor HRO761 with synthetic lethality in MSI cancers

Author

Ferretti, Stephane, Hamon, Jacques, de Kanter, Ruben, Scheufler, Clemens, Andraos-Rey, Rita, Barbe, Stephanie, Bechter, Elisabeth, Blank, Jutta, Bordas, Vincent, Dammassa, Ernesta, Decker, Andrea, Di Nanni, Noemi, Dourdoigne, Marion, Gavioli, Elena, Hattenberger, Marc, Heuser, Alisa, Hemmerlin, Christelle, Hinrichs, Jürgen, Kerr, Grainne, Laborde, Laurent, Jaco, Isabel, Núñez, Eloísa Jiménez, Martus, Hans-Joerg, Quadt, Cornelia, Reschke, Markus, Romanet, Vincent, Schaeffer, Fanny, Schoepfer, Joseph, Schrapp, Maxime, Strang, Ross, Voshol, Hans, Wartmann, Markus, Welly, Sarah, Zécri, Frédéric, Hofmann, Francesco, Möbitz, Henrik, and Cortés-Cros, Marta

Published
2024
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3. INPP5A phosphatase is a synthetic lethal target in GNAQ and GNA11-mutant melanomas

Author

Elbatsh, Ahmed M. O., Amin-Mansour, Ali, Haberkorn, Anne, Textor, Claudia, Ebel, Nicolas, Renard, Emilie, Koch, Lisa M., Groenveld, Femke C., Piquet, Michelle, Naumann, Ulrike, Ruddy, David A., Romanet, Vincent, Martínez Gómez, Julia M., Shirley, Matthew D., Wipfli, Peter, Schnell, Christian, Wartmann, Markus, Rausch, Martin, Jager, Martine J., Levesque, Mitchell P., Maira, Sauveur-Michel, and Manchado, Eusebio

Published
2024
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4. Author Correction: Direct and selective pharmacological disruption of the YAP–TEAD interface by IAG933 inhibits Hippo-dependent and RAS–MAPK-altered cancers

Author

Chapeau, Emilie A., Sansregret, Laurent, Galli, Giorgio G., Chène, Patrick, Wartmann, Markus, Mourikis, Thanos P., Jaaks, Patricia, Baltschukat, Sabrina, Barbosa, Ines A. M., Bauer, Daniel, Brachmann, Saskia M., Delaunay, Clara, Estadieu, Claire, Faris, Jason E., Furet, Pascal, Harlfinger, Stefanie, Hueber, Andreas, Jiménez Núñez, Eloísa, Kodack, David P., Mandon, Emeline, Martin, Typhaine, Mesrouze, Yannick, Romanet, Vincent, Scheufler, Clemens, Sellner, Holger, Stamm, Christelle, Sterker, Dario, Tordella, Luca, Hofmann, Francesco, Soldermann, Nicolas, and Schmelzle, Tobias

Published
2024
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5. K-RAS mutant pancreatic tumors show higher sensitivity to MEK than to PI3K inhibition in vivo.

Author

Hofmann, Irmgard, Weiss, Andreas, Elain, Gaelle, Schwaederle, Maria, Sterker, Dario, Romanet, Vincent, Schmelzle, Tobias, Lai, Albert, Brachmann, Saskia M, Bentires-Alj, Mohamed, Roberts, Thomas M, Sellers, William R, Hofmann, Francesco, and Maira, Sauveur-Michel

Subjects
Cell Line, Tumor, Animals, Humans, Mice, Mice, Nude, Pancreatic Neoplasms, Sulfonamides, Indazoles, Benzimidazoles, ras Proteins, Mitogen-Activated Protein Kinase Kinases, Extracellular Signal-Regulated MAP Kinases, Proto-Oncogene Proteins, Protein Kinase Inhibitors, Xenograft Model Antitumor Assays, Cell Proliferation, Phosphorylation, Mutation, Models, Biological, Female, Proto-Oncogene Proteins p21(ras), Proto-Oncogene Proteins c-akt, Gene Knockdown Techniques, Phosphatidylinositol 3-Kinases, HEK293 Cells, Phosphoinositide-3 Kinase Inhibitors, Cell Line, Tumor, Nude, Models, Biological, General Science & Technology
Abstract

Activating K-RAS mutations occur at a frequency of 90% in pancreatic cancer, and to date no therapies exist targeting this oncogene. K-RAS signals via downstream effector pathways such as the MAPK and the PI3K signaling pathways, and much effort has been focused on developing drugs targeting components of these pathways. To better understand the requirements for K-RAS and its downstream signaling pathways MAPK and PI3K in pancreatic tumor maintenance, we established an inducible K-RAS knock down system that allowed us to ablate K-RAS in established tumors. Knock down of K-RAS resulted in impaired tumor growth in all pancreatic xenograft models tested, demonstrating that K-RAS expression is indeed required for tumor maintenance of K-RAS mutant pancreatic tumors. We further examined signaling downstream of K-RAS, and detected a robust reduction of pERK levels upon K-RAS knock down. In contrast, no effect on pAKT levels could be observed due to almost undetectable basal expression levels. To investigate the requirement of the MAPK and the PI3K pathways on tumor maintenance, three selected pancreatic xenograft models were tested for their response to MEK or PI3K inhibition. Tumors of all three models regressed upon MEK inhibition, but showed less pronounced response to PI3K inhibition. The effect of MEK inhibition on pancreatic xenografts could be enhanced further by combined application of a PI3K inhibitor. These data provide further rationale for testing combinations of MEK and PI3K inhibitors in clinical trials comprising a patient population with pancreatic cancer harboring mutations in K-RAS.

Published
2012

6. Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf−/− mouse model

Author

Chapeau, Emilie A., Gembarska, Agnieszka, Durand, Eric Y., Mandon, Emeline, Estadieu, Claire, Romanet, Vincent, Wiesmann, Marion, Tiedt, Ralph, Lehar, Joseph, deWeck, Antoine, Rad, Roland, Barys, Louise, Jeay, Sebastien, Ferretti, Stephane, Kauffmann, Audrey, Sutter, Esther, Grevot, Armelle, Moulin, Pierre, Murakami, Masato, Sellers, William R., Hofmann, Francesco, and Jensen, Michael Rugaard

Published
2017

7. PI3K inhibition circumvents resistance to SHP2 blockade in metastatic triple-negative breast cancer

Author

Amante, Romain J., primary, Jehanno, Charly, additional, De Silva, Duvini, additional, Coissieux, Marie-May, additional, Ackerknecht, Markus, additional, Romanet, Vincent, additional, Sethi, Atul, additional, Hamelin, Baptiste, additional, Preca, Bogdan-Tiberius, additional, Piscuoglio, Salvatore, additional, Ng, Charlotte K. Y., additional, Mohseni, Morvarid, additional, and Bentires-Alj, Mohamed, additional

Published
2023
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8. Supplementary Figure 4 from Characterization of the Mechanism of Action of the Pan Class I PI3K Inhibitor NVP-BKM120 across a Broad Range of Concentrations

Author

Brachmann, Saskia M., primary, Kleylein-Sohn, Julia, primary, Gaulis, Swann, primary, Kauffmann, Audrey, primary, Blommers, Marcel J.J., primary, Kazic-Legueux, Malika, primary, Laborde, Laurent, primary, Hattenberger, Marc, primary, Stauffer, Fabian, primary, Vaxelaire, Juliane, primary, Romanet, Vincent, primary, Henry, Chrystèle, primary, Murakami, Masato, primary, Guthy, Daniel Alexander, primary, Sterker, Dario, primary, Bergling, Sebastian, primary, Wilson, Christopher, primary, Brümmendorf, Thomas, primary, Fritsch, Christine, primary, Garcia-Echeverria, Carlos, primary, Sellers, William R., primary, Hofmann, Francesco, primary, and Maira, Sauveur-Michel, primary

Published
2023
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9. Supplementary Figure 2 from Characterization of the Mechanism of Action of the Pan Class I PI3K Inhibitor NVP-BKM120 across a Broad Range of Concentrations

Author

Brachmann, Saskia M., primary, Kleylein-Sohn, Julia, primary, Gaulis, Swann, primary, Kauffmann, Audrey, primary, Blommers, Marcel J.J., primary, Kazic-Legueux, Malika, primary, Laborde, Laurent, primary, Hattenberger, Marc, primary, Stauffer, Fabian, primary, Vaxelaire, Juliane, primary, Romanet, Vincent, primary, Henry, Chrystèle, primary, Murakami, Masato, primary, Guthy, Daniel Alexander, primary, Sterker, Dario, primary, Bergling, Sebastian, primary, Wilson, Christopher, primary, Brümmendorf, Thomas, primary, Fritsch, Christine, primary, Garcia-Echeverria, Carlos, primary, Sellers, William R., primary, Hofmann, Francesco, primary, and Maira, Sauveur-Michel, primary

Published
2023
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10. Supplementary Figure 3 from Characterization of the Mechanism of Action of the Pan Class I PI3K Inhibitor NVP-BKM120 across a Broad Range of Concentrations

Author

Brachmann, Saskia M., primary, Kleylein-Sohn, Julia, primary, Gaulis, Swann, primary, Kauffmann, Audrey, primary, Blommers, Marcel J.J., primary, Kazic-Legueux, Malika, primary, Laborde, Laurent, primary, Hattenberger, Marc, primary, Stauffer, Fabian, primary, Vaxelaire, Juliane, primary, Romanet, Vincent, primary, Henry, Chrystèle, primary, Murakami, Masato, primary, Guthy, Daniel Alexander, primary, Sterker, Dario, primary, Bergling, Sebastian, primary, Wilson, Christopher, primary, Brümmendorf, Thomas, primary, Fritsch, Christine, primary, Garcia-Echeverria, Carlos, primary, Sellers, William R., primary, Hofmann, Francesco, primary, and Maira, Sauveur-Michel, primary

Published
2023
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11. Supplementary Figure 6 from Characterization of the Mechanism of Action of the Pan Class I PI3K Inhibitor NVP-BKM120 across a Broad Range of Concentrations

Author

Brachmann, Saskia M., primary, Kleylein-Sohn, Julia, primary, Gaulis, Swann, primary, Kauffmann, Audrey, primary, Blommers, Marcel J.J., primary, Kazic-Legueux, Malika, primary, Laborde, Laurent, primary, Hattenberger, Marc, primary, Stauffer, Fabian, primary, Vaxelaire, Juliane, primary, Romanet, Vincent, primary, Henry, Chrystèle, primary, Murakami, Masato, primary, Guthy, Daniel Alexander, primary, Sterker, Dario, primary, Bergling, Sebastian, primary, Wilson, Christopher, primary, Brümmendorf, Thomas, primary, Fritsch, Christine, primary, Garcia-Echeverria, Carlos, primary, Sellers, William R., primary, Hofmann, Francesco, primary, and Maira, Sauveur-Michel, primary

Published
2023
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12. Supplementary Methods, Table 1, and Figure Legends from Characterization of the Mechanism of Action of the Pan Class I PI3K Inhibitor NVP-BKM120 across a Broad Range of Concentrations

Author

Brachmann, Saskia M., primary, Kleylein-Sohn, Julia, primary, Gaulis, Swann, primary, Kauffmann, Audrey, primary, Blommers, Marcel J.J., primary, Kazic-Legueux, Malika, primary, Laborde, Laurent, primary, Hattenberger, Marc, primary, Stauffer, Fabian, primary, Vaxelaire, Juliane, primary, Romanet, Vincent, primary, Henry, Chrystèle, primary, Murakami, Masato, primary, Guthy, Daniel Alexander, primary, Sterker, Dario, primary, Bergling, Sebastian, primary, Wilson, Christopher, primary, Brümmendorf, Thomas, primary, Fritsch, Christine, primary, Garcia-Echeverria, Carlos, primary, Sellers, William R., primary, Hofmann, Francesco, primary, and Maira, Sauveur-Michel, primary

Published
2023
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13. Data from JAK–STAT Pathway Activation in Malignant and Nonmalignant Cells Contributes to MPN Pathogenesis and Therapeutic Response

Author

Kleppe, Maria, primary, Kwak, Minsuk, primary, Koppikar, Priya, primary, Riester, Markus, primary, Keller, Matthew, primary, Bastian, Lennart, primary, Hricik, Todd, primary, Bhagwat, Neha, primary, McKenney, Anna Sophia, primary, Papalexi, Efthymia, primary, Abdel-Wahab, Omar, primary, Rampal, Raajit, primary, Marubayashi, Sachie, primary, Chen, Jonathan J., primary, Romanet, Vincent, primary, Fridman, Jordan S., primary, Bromberg, Jacqueline, primary, Teruya-Feldstein, Julie, primary, Murakami, Masato, primary, Radimerski, Thomas, primary, Michor, Franziska, primary, Fan, Rong, primary, and Levine, Ross L., primary

Published
2023
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14. Supplementary Figure 7 from Characterization of the Mechanism of Action of the Pan Class I PI3K Inhibitor NVP-BKM120 across a Broad Range of Concentrations

Author

Brachmann, Saskia M., primary, Kleylein-Sohn, Julia, primary, Gaulis, Swann, primary, Kauffmann, Audrey, primary, Blommers, Marcel J.J., primary, Kazic-Legueux, Malika, primary, Laborde, Laurent, primary, Hattenberger, Marc, primary, Stauffer, Fabian, primary, Vaxelaire, Juliane, primary, Romanet, Vincent, primary, Henry, Chrystèle, primary, Murakami, Masato, primary, Guthy, Daniel Alexander, primary, Sterker, Dario, primary, Bergling, Sebastian, primary, Wilson, Christopher, primary, Brümmendorf, Thomas, primary, Fritsch, Christine, primary, Garcia-Echeverria, Carlos, primary, Sellers, William R., primary, Hofmann, Francesco, primary, and Maira, Sauveur-Michel, primary

Published
2023
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15. Data from Characterization of the Mechanism of Action of the Pan Class I PI3K Inhibitor NVP-BKM120 across a Broad Range of Concentrations

Author

Brachmann, Saskia M., primary, Kleylein-Sohn, Julia, primary, Gaulis, Swann, primary, Kauffmann, Audrey, primary, Blommers, Marcel J.J., primary, Kazic-Legueux, Malika, primary, Laborde, Laurent, primary, Hattenberger, Marc, primary, Stauffer, Fabian, primary, Vaxelaire, Juliane, primary, Romanet, Vincent, primary, Henry, Chrystèle, primary, Murakami, Masato, primary, Guthy, Daniel Alexander, primary, Sterker, Dario, primary, Bergling, Sebastian, primary, Wilson, Christopher, primary, Brümmendorf, Thomas, primary, Fritsch, Christine, primary, Garcia-Echeverria, Carlos, primary, Sellers, William R., primary, Hofmann, Francesco, primary, and Maira, Sauveur-Michel, primary

Published
2023
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16. Supplementary Figures 1 - 15, Tables 1 - 2 from JAK–STAT Pathway Activation in Malignant and Nonmalignant Cells Contributes to MPN Pathogenesis and Therapeutic Response

Author

Kleppe, Maria, primary, Kwak, Minsuk, primary, Koppikar, Priya, primary, Riester, Markus, primary, Keller, Matthew, primary, Bastian, Lennart, primary, Hricik, Todd, primary, Bhagwat, Neha, primary, McKenney, Anna Sophia, primary, Papalexi, Efthymia, primary, Abdel-Wahab, Omar, primary, Rampal, Raajit, primary, Marubayashi, Sachie, primary, Chen, Jonathan J., primary, Romanet, Vincent, primary, Fridman, Jordan S., primary, Bromberg, Jacqueline, primary, Teruya-Feldstein, Julie, primary, Murakami, Masato, primary, Radimerski, Thomas, primary, Michor, Franziska, primary, Fan, Rong, primary, and Levine, Ross L., primary

Published
2023
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17. Supplementary Figure 1 from Characterization of the Mechanism of Action of the Pan Class I PI3K Inhibitor NVP-BKM120 across a Broad Range of Concentrations

Author

Brachmann, Saskia M., primary, Kleylein-Sohn, Julia, primary, Gaulis, Swann, primary, Kauffmann, Audrey, primary, Blommers, Marcel J.J., primary, Kazic-Legueux, Malika, primary, Laborde, Laurent, primary, Hattenberger, Marc, primary, Stauffer, Fabian, primary, Vaxelaire, Juliane, primary, Romanet, Vincent, primary, Henry, Chrystèle, primary, Murakami, Masato, primary, Guthy, Daniel Alexander, primary, Sterker, Dario, primary, Bergling, Sebastian, primary, Wilson, Christopher, primary, Brümmendorf, Thomas, primary, Fritsch, Christine, primary, Garcia-Echeverria, Carlos, primary, Sellers, William R., primary, Hofmann, Francesco, primary, and Maira, Sauveur-Michel, primary

Published
2023
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18. PI3K inhibition circumvents resistance to SHP2 blockade in metastatic triple-negative breast cancer

Author

Amante, Romain J, Jehanno, Charly, De Silva, Duvini, Coissieux, Marie-May, Ackerknecht, Markus, Romanet, Vincent, Sethi, Atul, Hamelin, Baptiste, Preca, Bogdan-Tiberius, Piscuoglio, Salvatore, Ng, Charlotte K Y, Mohseni, Morvarid, and Bentires-Alj, Mohamed

Subjects
610 Medicine & health
Abstract

The protein tyrosine phosphatase SHP2 activates oncogenic pathways downstream of most receptor tyrosine kinases (RTK) and has been implicated in various cancer types, including the highly aggressive subtype of triple-negative breast cancer (TNBC). Although allosteric inhibitors of SHP2 have been developed and are currently being evaluated in clinical trials, neither the mechanisms of the resistance to these agents, nor the means to circumvent such resistance have been clearly defined. The PI3K signaling pathway is also hyperactivated in breast cancer and contributes to resistance to anticancer therapies. When PI3K is inhibited, resistance also develops for example via activation of RTKs. We therefore assessed the effect of targeting PI3K and SHP2 alone or in combination in preclinical models of metastatic TNBC. In addition to the beneficial inhibitory effects of SHP2 alone, dual PI3K/SHP2 treatment decreased primary tumor growth synergistically, blocked the formation of lung metastases, and increased survival in preclinical models. Mechanistically, transcriptome and phospho-proteome analyses revealed that resistance to SHP2 inhibition is mediated by PDGFRβ-evoked activation of PI3K signaling. Altogether, our data provide a rationale for co-targeting of SHP2 and PI3K in metastatic TNBC.

Published
2023

19. Data File S1 from Dose and Schedule Determine Distinct Molecular Mechanisms Underlying the Efficacy of the p53–MDM2 Inhibitor HDM201

Author

Jeay, Sébastien, primary, Ferretti, Stéphane, primary, Holzer, Philipp, primary, Fuchs, Jeanette, primary, Chapeau, Emilie A., primary, Wartmann, Markus, primary, Sterker, Dario, primary, Romanet, Vincent, primary, Murakami, Masato, primary, Kerr, Grainne, primary, Durand, Eric Y., primary, Gaulis, Swann, primary, Cortes-Cros, Marta, primary, Ruetz, Stephan, primary, Stachyra, Therese-Marie, primary, Kallen, Joerg, primary, Furet, Pascal, primary, Würthner, Jens, primary, Guerreiro, Nelson, primary, Halilovic, Ensar, primary, Jullion, Astrid, primary, Kauffmann, Audrey, primary, Kuriakose, Emil, primary, Wiesmann, Marion, primary, Jensen, Michael R., primary, Hofmann, Francesco, primary, and Sellers, William R., primary

Published
2023
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20. Data from Dose and Schedule Determine Distinct Molecular Mechanisms Underlying the Efficacy of the p53–MDM2 Inhibitor HDM201

Author

Jeay, Sébastien, primary, Ferretti, Stéphane, primary, Holzer, Philipp, primary, Fuchs, Jeanette, primary, Chapeau, Emilie A., primary, Wartmann, Markus, primary, Sterker, Dario, primary, Romanet, Vincent, primary, Murakami, Masato, primary, Kerr, Grainne, primary, Durand, Eric Y., primary, Gaulis, Swann, primary, Cortes-Cros, Marta, primary, Ruetz, Stephan, primary, Stachyra, Therese-Marie, primary, Kallen, Joerg, primary, Furet, Pascal, primary, Würthner, Jens, primary, Guerreiro, Nelson, primary, Halilovic, Ensar, primary, Jullion, Astrid, primary, Kauffmann, Audrey, primary, Kuriakose, Emil, primary, Wiesmann, Marion, primary, Jensen, Michael R., primary, Hofmann, Francesco, primary, and Sellers, William R., primary

Published
2023
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21. Supplementary Materials from JAK1/2 and Pan-Deacetylase Inhibitor Combination Therapy Yields Improved Efficacy in Preclinical Mouse Models of JAK2V617F-Driven Disease

Author

Evrot, Emeline, primary, Ebel, Nicolas, primary, Romanet, Vincent, primary, Roelli, Claudia, primary, Andraos, Rita, primary, Qian, Zhiyan, primary, Dölemeyer, Arno, primary, Dammassa, Ernesta, primary, Sterker, Dario, primary, Cozens, Robert, primary, Hofmann, Francesco, primary, Murakami, Masato, primary, Baffert, Fabienne, primary, and Radimerski, Thomas, primary

Published
2023
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22. Supplementary material, methods and data from Dose and Schedule Determine Distinct Molecular Mechanisms Underlying the Efficacy of the p53–MDM2 Inhibitor HDM201

Author

Jeay, Sébastien, primary, Ferretti, Stéphane, primary, Holzer, Philipp, primary, Fuchs, Jeanette, primary, Chapeau, Emilie A., primary, Wartmann, Markus, primary, Sterker, Dario, primary, Romanet, Vincent, primary, Murakami, Masato, primary, Kerr, Grainne, primary, Durand, Eric Y., primary, Gaulis, Swann, primary, Cortes-Cros, Marta, primary, Ruetz, Stephan, primary, Stachyra, Therese-Marie, primary, Kallen, Joerg, primary, Furet, Pascal, primary, Würthner, Jens, primary, Guerreiro, Nelson, primary, Halilovic, Ensar, primary, Jullion, Astrid, primary, Kauffmann, Audrey, primary, Kuriakose, Emil, primary, Wiesmann, Marion, primary, Jensen, Michael R., primary, Hofmann, Francesco, primary, and Sellers, William R., primary

Published
2023
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26. Supplemental Material, sj-docx-2-tpx-10.1177_0192623321993425 - HistoNet: A Deep Learning-Based Model of Normal Histology

Author

Hoefling, Holger, Sing, Tobias, Hossain, Imtiaz, Boisclair, Julie, Doelemeyer, Arno, Flandre, Thierry, Piaia, Alessandro, Romanet, Vincent, Santarossa, Gianluca, Chandrassegar Saravanan, Sutter, Esther, Turner, Oliver, Wuersch, Kuno, and Moulin, Pierre

Subjects
FOS: Clinical medicine, 111599 Pharmacology and Pharmaceutical Sciences not elsewhere classified
Abstract

Supplemental Material, sj-docx-2-tpx-10.1177_0192623321993425 for HistoNet: A Deep Learning-Based Model of Normal Histology by Holger Hoefling, Tobias Sing, Imtiaz Hossain, Julie Boisclair, Arno Doelemeyer, Thierry Flandre, Alessandro Piaia, Vincent Romanet, Gianluca Santarossa, Chandrassegar Saravanan, Esther Sutter, Oliver Turner, Kuno Wuersch and Pierre Moulin in Toxicologic Pathology

Published
2021
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27. Supplemental Material, sj-docx-1-tpx-10.1177_0192623321993425 - HistoNet: A Deep Learning-Based Model of Normal Histology

Author

Hoefling, Holger, Sing, Tobias, Hossain, Imtiaz, Boisclair, Julie, Doelemeyer, Arno, Flandre, Thierry, Piaia, Alessandro, Romanet, Vincent, Santarossa, Gianluca, Chandrassegar Saravanan, Sutter, Esther, Turner, Oliver, Wuersch, Kuno, and Moulin, Pierre

Subjects
FOS: Clinical medicine, 111599 Pharmacology and Pharmaceutical Sciences not elsewhere classified
Abstract

Supplemental Material, sj-docx-1-tpx-10.1177_0192623321993425 for HistoNet: A Deep Learning-Based Model of Normal Histology by Holger Hoefling, Tobias Sing, Imtiaz Hossain, Julie Boisclair, Arno Doelemeyer, Thierry Flandre, Alessandro Piaia, Vincent Romanet, Gianluca Santarossa, Chandrassegar Saravanan, Esther Sutter, Oliver Turner, Kuno Wuersch and Pierre Moulin in Toxicologic Pathology

Published
2021
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28. HistoNet: A Deep Learning-Based Model of Normal Histology

Author

Hoefling, Holger, primary, Sing, Tobias, additional, Hossain, Imtiaz, additional, Boisclair, Julie, additional, Doelemeyer, Arno, additional, Flandre, Thierry, additional, Piaia, Alessandro, additional, Romanet, Vincent, additional, Santarossa, Gianluca, additional, Saravanan, Chandrassegar, additional, Sutter, Esther, additional, Turner, Oliver, additional, Wuersch, Kuno, additional, and Moulin, Pierre, additional

Published
2021
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29. A deep learning-based model of normal histology

Author

Sing, Tobias, primary, Hoefling, Holger, additional, Hossain, Imtiaz, additional, Boisclair, Julie, additional, Doelemeyer, Arno, additional, Flandre, Thierry, additional, Piaia, Alessandro, additional, Romanet, Vincent, additional, Santarossa, Gianluca, additional, Saravanan, Chandrassegar, additional, Sutter, Esther, additional, Turner, Oliver, additional, Wuersch, Kuno, additional, and Moulin, Pierre, additional

Published
2019
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30. A conditional inducible JAK2V617F transgenic mouse model reveals myeloproliferative disease that is reversible upon switching off transgene expression

Author

Chapeau, Emilie A., primary, Mandon, Emeline, additional, Gill, Jason, additional, Romanet, Vincent, additional, Ebel, Nicolas, additional, Powajbo, Violetta, additional, Andraos-Rey, Rita, additional, Qian, Zhiyan, additional, Kininis, Miltos, additional, Zumstein-Mecker, Sabine, additional, Ito, Moriko, additional, Hynes, Nancy E., additional, Tiedt, Ralph, additional, Hofmann, Francesco, additional, Eshkind, Leonid, additional, Bockamp, Ernesto, additional, Kinzel, Bernd, additional, Mueller, Matthias, additional, Murakami, Masato, additional, Baffert, Fabienne, additional, and Radimerski, Thomas, additional

Published
2019
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31. Dose and Schedule Determine Distinct Molecular Mechanisms Underlying the Efficacy of the p53–MDM2 Inhibitor HDM201

Author

Jeay, Sébastien, primary, Ferretti, Stéphane, additional, Holzer, Philipp, additional, Fuchs, Jeanette, additional, Chapeau, Emilie A., additional, Wartmann, Markus, additional, Sterker, Dario, additional, Romanet, Vincent, additional, Murakami, Masato, additional, Kerr, Grainne, additional, Durand, Eric Y., additional, Gaulis, Swann, additional, Cortes-Cros, Marta, additional, Ruetz, Stephan, additional, Stachyra, Therese-Marie, additional, Kallen, Joerg, additional, Furet, Pascal, additional, Würthner, Jens, additional, Guerreiro, Nelson, additional, Halilovic, Ensar, additional, Jullion, Astrid, additional, Kauffmann, Audrey, additional, Kuriakose, Emil, additional, Wiesmann, Marion, additional, Jensen, Michael R., additional, Hofmann, Francesco, additional, and Sellers, William R., additional

Published
2018
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32. A conditional inducible JAK2V617F transgenic mouse model reveals myeloproliferative disease that is reversible upon switching off transgene expression.

Author

Chapeau, Emilie A., Mandon, Emeline, Gill, Jason, Romanet, Vincent, Ebel, Nicolas, Powajbo, Violetta, Andraos-Rey, Rita, Qian, Zhiyan, Kininis, Miltos, Zumstein-Mecker, Sabine, Ito, Moriko, Hynes, Nancy E., Tiedt, Ralph, Hofmann, Francesco, Eshkind, Leonid, Bockamp, Ernesto, Kinzel, Bernd, Mueller, Matthias, Murakami, Masato, and Baffert, Fabienne

Subjects
TRANSGENIC mice, HEMATOPOIETIC stem cells, POLYCYTHEMIA vera, BONE marrow cells, TRANSGENE expression, DISEASES
Abstract

Aberrant activation of the JAK/STAT pathway is thought to be the critical event in the pathogenesis of the chronic myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia and primary myelofibrosis. The most frequent genetic alteration in these pathologies is the activating JAK2V617F mutation, and expression of the mutant gene in mouse models was shown to cause a phenotype resembling the human diseases. Given the body of genetic evidence, it has come as a sobering finding that JAK inhibitor therapy only modestly suppresses the JAK2V617F allele burden, despite showing clear benefits in terms of reducing splenomegaly and constitutional symptoms in patients. To gain a better understanding if JAK2V617F is required for maintenance of myeloproliferative disease once it has evolved, we generated a conditional inducible transgenic JAK2V617F mouse model using the SCL-tTA-2S tet-off system. Our model corroborates that expression of JAK2V617F in hematopoietic stem and progenitor cells recapitulates key hallmarks of human myeloproliferative neoplasms, and exhibits gender differences in disease manifestation. The disease was found to be transplantable, and importantly, reversible when transgenic JAK2V617F expression was switched off. Our results indicate that mutant JAK2V617F-specific inhibitors should result in profound disease modification by disabling the myeloproliferative clone bearing mutant JAK2. [ABSTRACT FROM AUTHOR]

Published
2019
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33. Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf −/− mouse model

Author

Chapeau, Emilie A., primary, Gembarska, Agnieszka, additional, Durand, Eric Y., additional, Mandon, Emeline, additional, Estadieu, Claire, additional, Romanet, Vincent, additional, Wiesmann, Marion, additional, Tiedt, Ralph, additional, Lehar, Joseph, additional, de Weck, Antoine, additional, Rad, Roland, additional, Barys, Louise, additional, Jeay, Sebastien, additional, Ferretti, Stephane, additional, Kauffmann, Audrey, additional, Sutter, Esther, additional, Grevot, Armelle, additional, Moulin, Pierre, additional, Murakami, Masato, additional, Sellers, William R., additional, Hofmann, Francesco, additional, and Jensen, Michael Rugaard, additional

Published
2017
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34. CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative Neoplasms

Author

Meyer, Sara C., primary, Keller, Matthew D., additional, Chiu, Sophia, additional, Koppikar, Priya, additional, Guryanova, Olga A., additional, Rapaport, Franck, additional, Xu, Ke, additional, Manova, Katia, additional, Pankov, Dmitry, additional, O’Reilly, Richard J., additional, Kleppe, Maria, additional, McKenney, Anna Sophia, additional, Shih, Alan H., additional, Shank, Kaitlyn, additional, Ahn, Jihae, additional, Papalexi, Eftymia, additional, Spitzer, Barbara, additional, Socci, Nick, additional, Viale, Agnes, additional, Mandon, Emeline, additional, Ebel, Nicolas, additional, Andraos, Rita, additional, Rubert, Joëlle, additional, Dammassa, Ernesta, additional, Romanet, Vincent, additional, Dölemeyer, Arno, additional, Zender, Michael, additional, Heinlein, Melanie, additional, Rampal, Raajit, additional, Weinberg, Rona Singer, additional, Hoffman, Ronald, additional, Sellers, William R., additional, Hofmann, Francesco, additional, Murakami, Masato, additional, Baffert, Fabienne, additional, Gaul, Christoph, additional, Radimerski, Thomas, additional, and Levine, Ross L., additional

Published
2015
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35. Activity of the Type II JAK2 Inhibitor CHZ868 in B Cell Acute Lymphoblastic Leukemia

Author

Wu, Shuo-Chieh, primary, Li, Loretta S., additional, Kopp, Nadja, additional, Montero, Joan, additional, Chapuy, Bjoern, additional, Yoda, Akinori, additional, Christie, Amanda L., additional, Liu, Huiyun, additional, Christodoulou, Alexandra, additional, van Bodegom, Diederik, additional, van der Zwet, Jordy, additional, Layer, Jacob V., additional, Tivey, Trevor, additional, Lane, Andrew A., additional, Ryan, Jeremy A., additional, Ng, Samuel Y., additional, DeAngelo, Daniel J., additional, Stone, Richard M., additional, Steensma, David, additional, Wadleigh, Martha, additional, Harris, Marian, additional, Mandon, Emeline, additional, Ebel, Nicolas, additional, Andraos, Rita, additional, Romanet, Vincent, additional, Dölemeyer, Arno, additional, Sterker, Dario, additional, Zender, Michael, additional, Rodig, Scott J., additional, Murakami, Masato, additional, Hofmann, Francesco, additional, Kuo, Frank, additional, Eck, Michael J., additional, Silverman, Lewis B., additional, Sallan, Stephen E., additional, Letai, Anthony, additional, Baffert, Fabienne, additional, Vangrevelinghe, Eric, additional, Radimerski, Thomas, additional, Gaul, Christoph, additional, and Weinstock, David M., additional

Published
2015
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36. JAK–STAT Pathway Activation in Malignant and Nonmalignant Cells Contributes to MPN Pathogenesis and Therapeutic Response

Author

Kleppe, Maria, primary, Kwak, Minsuk, additional, Koppikar, Priya, additional, Riester, Markus, additional, Keller, Matthew, additional, Bastian, Lennart, additional, Hricik, Todd, additional, Bhagwat, Neha, additional, McKenney, Anna Sophia, additional, Papalexi, Efthymia, additional, Abdel-Wahab, Omar, additional, Rampal, Raajit, additional, Marubayashi, Sachie, additional, Chen, Jonathan J., additional, Romanet, Vincent, additional, Fridman, Jordan S., additional, Bromberg, Jacqueline, additional, Teruya-Feldstein, Julie, additional, Murakami, Masato, additional, Radimerski, Thomas, additional, Michor, Franziska, additional, Fan, Rong, additional, and Levine, Ross L., additional

Published
2015
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37. Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf-/- mouse model.

Author

Chapeau, Emilie A., Gembarska, Agnieszka, Durand, Eric Y., Mandon, Emeline, Estadieu, Claire, Romanet, Vincent, Wiesmann, Marion, Tiedt, Ralph, Lehar, Joseph, de Weck, Antoine, Rad, Roland, Barys, Louise, Jeay, Sebastien, Ferretti, Stephane, Kauffmann, Audrey, Sutter, Esther, Grevot, Armelle, Moulin, Pierre, Murakami, Masato, and Sellers, William R.

Subjects
MUTAGENESIS, LABORATORY mice, TRANSPOSONS, COHORT analysis, PHARMACOLOGY
Abstract

Inhibitors of double minute 2 protein (MDM2)-tumor protein 53 (TP53) interaction are predicted to be effective in tumors in which the TP53 gene is wild type, by preventing TP53 protein degradation. One such setting is represented by the frequent CDKN2A deletion in human cancer that, through inactivation of p14ARF, activates MDM2 protein, which in turn degrades TP53 tumor suppressor. Here we used piggyBac (PB) transposon insertional mutagenesis to anticipate resistance mechanisms occurring during treatment with the MDM2-TP53 inhibitor HDM201. Constitutive PB mutagenesis in Arf-/- mice provided a collection of spontaneous tumors with characterized insertional genetic landscapes. Tumors were allografted in large cohorts of mice to assess the pharmacologic effects of HDM201. Sixteen out of 21 allograft models were sensitive to HDM201 but ultimately relapsed under treatment. A comparison of tumors with acquired resistance to HDM201 and untreated tumors identified 87 genes that were differentially and significantly targeted by the PB transposon. Resistant tumors displayed a complex clonality pattern suggesting the emergence of several resistant subclones. Among the most frequent alterations conferring resistance, we observed somatic and insertional loss-of-function mutations in transformation-related protein 53 (Trp53) in 54% of tumors and transposonmediated gain-of-function alterations in B-cell lymphoma-extra large (Bcl-xL), Mdm4, and two TP53 family members, resulting in expression of the TP53 dominant negative truncations △NTrp63 and △NTrp73. Enhanced BCL-xL and MDM4 protein expression was confirmed in resistant tumors, as well as in HDM201-resistant patient-derived tumor xenografts. Interestingly, concomitant inhibition of MDM2 and BCL-xL demonstrated significant synergy in p53 wild-type cell lines in vitro. Collectively, our findings identify several potential mechanisms by which TP53 wild-type tumors may escape MDM2-targeted therapy. [ABSTRACT FROM AUTHOR]

Published
2017
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39. JAK1/2 and Pan-Deacetylase Inhibitor Combination Therapy Yields Improved Efficacy in Preclinical Mouse Models of JAK2V617F-Driven Disease

Author

Evrot, Emeline, primary, Ebel, Nicolas, additional, Romanet, Vincent, additional, Roelli, Claudia, additional, Andraos, Rita, additional, Qian, Zhiyan, additional, Dölemeyer, Arno, additional, Dammassa, Ernesta, additional, Sterker, Dario, additional, Cozens, Robert, additional, Hofmann, Francesco, additional, Murakami, Masato, additional, Baffert, Fabienne, additional, and Radimerski, Thomas, additional

Published
2013
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40. Fibroblast Growth Factor Receptors as Novel Therapeutic Targets in SNF5-Deleted Malignant Rhabdoid Tumors

Author

Wöhrle, Simon, primary, Weiss, Andreas, additional, Ito, Moriko, additional, Kauffmann, Audrey, additional, Murakami, Masato, additional, Jagani, Zainab, additional, Thuery, Anne, additional, Bauer-Probst, Beatrice, additional, Reimann, Flavia, additional, Stamm, Christelle, additional, Pornon, Astrid, additional, Romanet, Vincent, additional, Guagnano, Vito, additional, Brümmendorf, Thomas, additional, Sellers, William R., additional, Hofmann, Francesco, additional, Roberts, Charles W. M., additional, and Graus Porta, Diana, additional

Published
2013
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42. Differential effects of hydroxyurea and INC424 on mutant allele burden and myeloproliferative phenotype in a JAK2-V617F polycythemia vera mouse model

Author

Kubovcakova, Lucia, primary, Lundberg, Pontus, additional, Grisouard, Jean, additional, Hao-Shen, Hui, additional, Romanet, Vincent, additional, Andraos, Rita, additional, Murakami, Masato, additional, Dirnhofer, Stephan, additional, Wagner, Kay-Uwe, additional, Radimerski, Thomas, additional, and Skoda, Radek C., additional

Published
2013
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43. Characterization of the Mechanism of Action of the Pan Class I PI3K Inhibitor NVP-BKM120 across a Broad Range of Concentrations

Author

Brachmann, Saskia M., primary, Kleylein-Sohn, Julia, additional, Gaulis, Swann, additional, Kauffmann, Audrey, additional, Blommers, Marcel J.J., additional, Kazic-Legueux, Malika, additional, Laborde, Laurent, additional, Hattenberger, Marc, additional, Stauffer, Fabian, additional, Vaxelaire, Juliane, additional, Romanet, Vincent, additional, Henry, Chrystèle, additional, Murakami, Masato, additional, Guthy, Daniel Alexander, additional, Sterker, Dario, additional, Bergling, Sebastian, additional, Wilson, Christopher, additional, Brümmendorf, Thomas, additional, Fritsch, Christine, additional, Garcia-Echeverria, Carlos, additional, Sellers, William R., additional, Hofmann, Francesco, additional, and Maira, Sauveur-Michel, additional

Published
2012
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44. Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition

Author

Weigert, Oliver, primary, Lane, Andrew A., additional, Bird, Liat, additional, Kopp, Nadja, additional, Chapuy, Bjoern, additional, van Bodegom, Diederik, additional, Toms, Angela V., additional, Marubayashi, Sachie, additional, Christie, Amanda L., additional, McKeown, Michael, additional, Paranal, Ronald M., additional, Bradner, James E., additional, Yoda, Akinori, additional, Gaul, Christoph, additional, Vangrevelinghe, Eric, additional, Romanet, Vincent, additional, Murakami, Masato, additional, Tiedt, Ralph, additional, Ebel, Nicolas, additional, Evrot, Emeline, additional, De Pover, Alain, additional, Régnier, Catherine H., additional, Erdmann, Dirk, additional, Hofmann, Francesco, additional, Eck, Michael J., additional, Sallan, Stephen E., additional, Levine, Ross L., additional, Kung, Andrew L., additional, Baffert, Fabienne, additional, Radimerski, Thomas, additional, and Weinstock, David M., additional

Published
2012
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45. HSP90 Inhibition Targets JAK2 and Is Highly Effective in CRLF2-Rearranged Acute Lymphoblastic Leukemia

Author

Weigert, Oliver, primary, Bird, Liat, additional, Kopp, Nadja, additional, Lane, Andrew A., additional, Chapuy, Bjoern, additional, van Bodegom, Diederik, additional, Marubayashi, Sachie, additional, Yoda, Akinori, additional, Romanet, Vincent, additional, Murakami, Masato, additional, Sallan, Stephen E., additional, Levine, Ross L, additional, Kung, Andrew L., additional, Radimerski, Thomas, additional, and Weinstock, David M, additional

Published
2011
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47. JAK2 exon 12mutant mice display isolated erythrocytosis and changes in iron metabolism favoring increased erythropoiesis

Author

Grisouard, Jean, Li, Sai, Kubovcakova, Lucia, Rao, Tata Nageswara, Meyer, Sara C., Lundberg, Pontus, Hao-Shen, Hui, Romanet, Vincent, Murakami, Masato, Radimerski, Thomas, Dirnhofer, Stephan, and Skoda, Radek C.

Abstract

Mutations in JAK2 exon 12are frequently found in patients with polycythemia vera (PV) that do not carry a JAK2-V617Fmutation. The majority of these patients display isolated erythrocytosis. We generated a mouse model that expresses JAK2-N542-E543del,the most frequent JAK2 exon 12mutation found in PV patients. Mice expressing the human JAK2-N542-E543del (Ex12)showed a strong increase in red blood cell parameters but normal neutrophil and platelet counts, and reduced overall survival. Erythropoiesis was increased in the bone marrow and spleen, with normal megakaryopoiesis and absence of myelofibrosis in histopathology. Erythroid progenitors and precursors were increased in hematopoietic tissues, but the numbers of megakaryocytic precursors were unchanged. Phosphorylation Stat3 and Erk1/2 proteins were increased, and a trend toward increased phospho-Stat5 and phospho-Stat1 was noted. However, Stat1 knock out in Ex12mice induced no changes in platelet or red cell parameters, indicating that Stat1 does not play a central role in mediating the effects of Ex12 signaling on megakaryopoiesis or erythropoiesis. Ex12mice showed decreased expression of hepcidinand increased expression of transferrin receptor-1and erythroferrone,suggesting that the strong erythroid phenotype in Ex12mutant mice is favored by changes in iron metabolism that optimize iron availability to allow maximal production of red cells.

Published
2016
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48. Tumour T1 changes in vivo are highly predictive of response to chemotherapy and reflect the number of viable tumour cells - a preclinical MR study in mice.

Author

Weidensteiner, Claudia, Allegrini, Peter R., Sticker-Jantscheff, Melanie, Romanet, Vincent, Ferretti, Stephane, and McSheehy, Paul M. J.

Subjects
CANCER chemotherapy, CANCER cells, MAGNETIC resonance imaging, LABORATORY mice, TREATMENT effectiveness, MTOR protein, CHOLINE, BIOLUMINESCENCE
Abstract

Background Effective chemotherapy rapidly reduces the spin--lattice relaxation of water protons (T1) in solid tumours and this change (ΔT1) often precedes and strongly correlates with the eventual change in tumour volume (TVol). To understand the biological nature of ΔT1, we have performed studies in vivo and ex vivo with the allosteric mTOR inhibitor, everolimus. Mice bearing RIF-1 tumours were studied by magnetic resonance imaging (MRI) to determine TVol and T1, and MR spectroscopy (MRS) to determine levels of the proliferation marker choline and levels of lipid apoptosis markers, prior to and 5 days (endpoint) after daily treatment with vehicle or everolimus (10 mg/kg). At the endpoint, tumours were ablated and an entire section analysed for cellular and necrotic quantification and staining for the proliferation antigen Ki67 and cleaved-caspase-3 as a measure of apoptosis. The number of blood-vessels (BV) was evaluated by CD31 staining. Mice bearing B16/BL6 melanoma tumours were studied by MRI to determine T1 under similar everolimus treatment. At the endpoint, cell bioluminescence of the tumours was measured ex vivo. Results Everolimus blocked RIF-1 tumour growth and significantly reduced tumour T1 and total choline (Cho) levels, and increased polyunsaturated fatty-acids which are markers of apoptosis. Immunohistochemistry showed that everolimus reduced the%Ki67+ cells but did not affect caspase-3 apoptosis, necrosis, BV-number or cell density. The change in T1 (ΔT1) correlated strongly with the changes in TVol and Cho and%Ki67+. In B16/BL6 tumours, everolimus also decreased T 1 and this correlated with cell bioluminescence; another marker of cell viability. Receiver-operating-characteristic curves (ROC) for everolimus on RIF-1 tumours showed that ΔT1 had very high levels of sensitivity and specificity (ROCAUC = 0.84) and this was confirmed for the cytotoxic patupilone in the same tumour model (ROCAUC = 0.97). Conclusion These studies suggest that ΔT1 is not a measure of cell density but reflects the decreased number of remaining viable and proliferating tumour cells due to perhaps cell and tissue destruction releasing proteins and/or metals that cause T1 relaxation. ΔT1 is a highly sensitive and specific predictor of response. This MRI method provides the opportunity to stratify a patient population during tumour therapy in the clinic. [ABSTRACT FROM AUTHOR]

Published
2014
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