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3. Inhibition of receptor tyrosine kinase signalling by small molecule agonist of T-cell protein tyrosine phosphatase

Author

Tähtinen Siri, Kohonen Pekka, Sahlberg Niko, Marttila Heidi, Mattila Elina, Halonen Pasi, Perälä Merja, and Ivaska Johanna

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

Abstract Background T-cell protein tyrosine phosphatase (TCPTP/TC45) is a ubiquitously expressed intra-cellular non-receptor protein tyrosine phosphatase involved in the negative regulation of several cancer relevant cellular signalling pathways. We have previously shown that interaction between the α-cytoplasmic tail of α1β1 integrin and TCPTP activates TCPTP by disrupting an inhibitory intra-molecular bond in TCPTP. Thus, inhibition of the regulatory interaction in TCPTP is a desirable strategy for TCPTP activation and attenuation of oncogenic RTK signalling. However, this is challenging with low molecular weight compounds. Methods We developed a high-throughput compatible assay to analyse activity of recombinant TCPTP in vitro. Using this assay we have screened 64280 small molecules to identify novel agonists for TCPTP. Dose-dependent response to TCPTP agonist was performed using the in vitro assay. Inhibition effects and specificity of TCPTP agonists were evaluated using TCPTP expressing and null mouse embryonic fibroblasts. Western blot analysis was used to evaluate attenuation of PDGFRβ and EGFR phosphorylation. Inhibition of VEGF signalling was analysed with VEGF-induced endothelial cell sprouting assays. Results From the screen we identified six TCPTP agonists. Two compounds competed with α1-cytoplasmic domain for binding to TCPTP, suggesting that they activate TCPTP similar to α1-cyt by disrupting the intra-molecular bond in TCPTP. Importantly, one of the compounds (spermidine) displayed specificity towards TCPTP in cells, since TCPTP -/- cells were 43-fold more resistant to the compound than TCPTP expressing cells. This compound attenuates PDGFRβ and VEGFR2 signalling in cells in a TCPTP-dependent manner and functions as a negative regulator of EGFR phosphorylation in cancer cells. Conclusions In this study we showed that small molecules mimicking TCPTP-α1 interaction can be used as TCPTP agonists. These data provide the first proof-of-concept description of the use of high-throughput screening to identify small molecule PTP activators that could function as RTK antagonists in cells.

Published
2010
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4. Neutrophils Kill Antibody-Opsonized Cancer Cells by Trogoptosis

Author

Matlung, Hanke L., Babes, Liane, Zhao, Xi Wen, van Houdt, Michel, Treffers, Louise W., van Rees, Dieke J., Franke, Katka, Schornagel, Karin, Verkuijlen, Paul, Janssen, Hans, Halonen, Pasi, Lieftink, Cor, Beijersbergen, Roderick L., Leusen, Jeanette H.W., Boelens, Jaap J., Kuhnle, Ingrid, van der Werff Ten Bosch, Jutte, Seeger, Karl, Rutella, Sergio, Pagliara, Daria, Matozaki, Takashi, Suzuki, Eiji, Menke-van der Houven van Oordt, Catharina Willemien, van Bruggen, Robin, Roos, Dirk, van Lier, Rene A.W., Kuijpers, Taco W., Kubes, Paul, van den Berg, Timo K., Matlung, Hanke L., Babes, Liane, Zhao, Xi Wen, van Houdt, Michel, Treffers, Louise W., van Rees, Dieke J., Franke, Katka, Schornagel, Karin, Verkuijlen, Paul, Janssen, Hans, Halonen, Pasi, Lieftink, Cor, Beijersbergen, Roderick L., Leusen, Jeanette H.W., Boelens, Jaap J., Kuhnle, Ingrid, van der Werff Ten Bosch, Jutte, Seeger, Karl, Rutella, Sergio, Pagliara, Daria, Matozaki, Takashi, Suzuki, Eiji, Menke-van der Houven van Oordt, Catharina Willemien, van Bruggen, Robin, Roos, Dirk, van Lier, Rene A.W., Kuijpers, Taco W., Kubes, Paul, and van den Berg, Timo K.

Published
2018

5. Neutrophils Kill Antibody-Opsonized Cancer Cells by Trogoptosis

Author

CTI Leusen, Infection & Immunity, PMC Medisch specialisten, CTI Nierkens, Matlung, Hanke L., Babes, Liane, Zhao, Xi Wen, van Houdt, Michel, Treffers, Louise W., van Rees, Dieke J., Franke, Katka, Schornagel, Karin, Verkuijlen, Paul, Janssen, Hans, Halonen, Pasi, Lieftink, Cor, Beijersbergen, Roderick L., Leusen, Jeanette H.W., Boelens, Jaap J., Kuhnle, Ingrid, van der Werff Ten Bosch, Jutte, Seeger, Karl, Rutella, Sergio, Pagliara, Daria, Matozaki, Takashi, Suzuki, Eiji, Menke-van der Houven van Oordt, Catharina Willemien, van Bruggen, Robin, Roos, Dirk, van Lier, Rene A.W., Kuijpers, Taco W., Kubes, Paul, van den Berg, Timo K., CTI Leusen, Infection & Immunity, PMC Medisch specialisten, CTI Nierkens, Matlung, Hanke L., Babes, Liane, Zhao, Xi Wen, van Houdt, Michel, Treffers, Louise W., van Rees, Dieke J., Franke, Katka, Schornagel, Karin, Verkuijlen, Paul, Janssen, Hans, Halonen, Pasi, Lieftink, Cor, Beijersbergen, Roderick L., Leusen, Jeanette H.W., Boelens, Jaap J., Kuhnle, Ingrid, van der Werff Ten Bosch, Jutte, Seeger, Karl, Rutella, Sergio, Pagliara, Daria, Matozaki, Takashi, Suzuki, Eiji, Menke-van der Houven van Oordt, Catharina Willemien, van Bruggen, Robin, Roos, Dirk, van Lier, Rene A.W., Kuijpers, Taco W., Kubes, Paul, and van den Berg, Timo K.

Published
2018

6. Neutrophils Kill Antibody-Opsonized Cancer Cells by Trogoptosis

Author

Matlung, Hanke L., primary, Babes, Liane, additional, Zhao, Xi Wen, additional, van Houdt, Michel, additional, Treffers, Louise W., additional, van Rees, Dieke J., additional, Franke, Katka, additional, Schornagel, Karin, additional, Verkuijlen, Paul, additional, Janssen, Hans, additional, Halonen, Pasi, additional, Lieftink, Cor, additional, Beijersbergen, Roderick L., additional, Leusen, Jeanette H.W., additional, Boelens, Jaap J., additional, Kuhnle, Ingrid, additional, van der Werff Ten Bosch, Jutte, additional, Seeger, Karl, additional, Rutella, Sergio, additional, Pagliara, Daria, additional, Matozaki, Takashi, additional, Suzuki, Eiji, additional, Menke-van der Houven van Oordt, Catharina Willemien, additional, van Bruggen, Robin, additional, Roos, Dirk, additional, van Lier, Rene A.W., additional, Kuijpers, Taco W., additional, Kubes, Paul, additional, and van den Berg, Timo K., additional

Published
2018
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7. Identification of a novel ATM inhibitor with cancer cell specific radiosensitization activity

Author

Dohmen, Amy J.C., primary, Qiao, Xiaohang, additional, Duursma, Anja, additional, Wijdeven, Ruud H., additional, Lieftink, Cor, additional, Hageman, Floor, additional, Morris, Ben, additional, Halonen, Pasi, additional, Vens, Conchita, additional, van den Brekel, Michiel W.M., additional, Ovaa, Huib, additional, Neefjes, Jacques, additional, and Zuur, Charlotte L., additional

Published
2017
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10. VAV3 mediates resistance to breast cancer endocrine therapy

Author

Aguilar, Helena, Urruticoechea, Ander, Halonen, Pasi, Kiyotani, Kazuma, Mushiroda, Taisei, Barril, Xavier, Serra-Musach, Jordi, Islam, Abul, Caizzi, Livia, Di Croce, Luciano, Nevedomskaya, Ekaterina, Zwart, Wilbert, Bostner, Josefine, Karlsson, Elin, Perez-Tenorio, Gizeh, Fornander, Tommy, Sgroi, Dennis C, Garcia-Mata, Rafael, Jansen, Maurice Phm, García, Nadia, Bonifaci, Núria, Climent, Fina, Soler, María Teresa, Rodríguez-Vida, Alejo, Gil, Miguel, Brunet, Joan, Martrat, Griselda, Gómez-Baldó, Laia, Extremera, Ana I, Figueras, Agnes, Balart, Josep, Clarke, Robert, Burnstein, Kerry L, Carlson, Kathryn E, Katzenellenbogen, John A, Vizoso, Miguel, Esteller, Manel, Villanueva, Alberto, Rodríguez-Peña, Ana B, Bustelo, Xosé R, Nakamura, Yusuke, Zembutsu, Hitoshi, Stål, Olle, Beijersbergen, Roderick L, Pujana, Miguel Angel, Aguilar, Helena, Urruticoechea, Ander, Halonen, Pasi, Kiyotani, Kazuma, Mushiroda, Taisei, Barril, Xavier, Serra-Musach, Jordi, Islam, Abul, Caizzi, Livia, Di Croce, Luciano, Nevedomskaya, Ekaterina, Zwart, Wilbert, Bostner, Josefine, Karlsson, Elin, Perez-Tenorio, Gizeh, Fornander, Tommy, Sgroi, Dennis C, Garcia-Mata, Rafael, Jansen, Maurice Phm, García, Nadia, Bonifaci, Núria, Climent, Fina, Soler, María Teresa, Rodríguez-Vida, Alejo, Gil, Miguel, Brunet, Joan, Martrat, Griselda, Gómez-Baldó, Laia, Extremera, Ana I, Figueras, Agnes, Balart, Josep, Clarke, Robert, Burnstein, Kerry L, Carlson, Kathryn E, Katzenellenbogen, John A, Vizoso, Miguel, Esteller, Manel, Villanueva, Alberto, Rodríguez-Peña, Ana B, Bustelo, Xosé R, Nakamura, Yusuke, Zembutsu, Hitoshi, Stål, Olle, Beijersbergen, Roderick L, and Pujana, Miguel Angel

Abstract

INTRODUCTION: Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor alpha (ERalpha) are among the most effective systemic treatments for ERalpha-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through mechanisms that involve ERalpha transcriptional regulatory plasticity. Here, we identify VAV3 as a critical component in this process. METHODS: A cell-based chemical compound screen was carried out to identify therapeutic strategies against resistance to endocrine therapy. Binding to ERalpha was evaluated by molecular docking analyses, an agonist fluoligand assay, and short-hairpin (sh) RNA-mediated protein depletion. Microarray analyses were performed to identify altered gene expression. Western blot of signaling and proliferation markers and shRNA-mediated protein depletion in viability and clonogenic assays were performed to delineate the role of VAV3. Genetic variation in VAV3 was assessed for association with the response to tamoxifen. Immunohistochemical analyses of VAV3 were carried out to determine the association with therapy response and different tumor markers. An analysis of gene expression association with drug sensitivity was carried out to identify a potential therapeutic approach based on differential VAV3 expression. RESULTS: The compound YC-1 was found to comparatively reduce the viability of cell models of acquired resistance. This effect was probably not due to activation of its canonical target (soluble guanylyl cyclase) but instead a result of binding to ERalpha. VAV3 was selectively reduced upon exposure to YC-1 or ERalpha depletion and, accordingly, VAV3 depletion comparatively reduced the viability of cell models of acquired resistance. In the clinical scenario, germline variation in VAV3 was associated with response to tamoxifen in Japanese breast cancer patients (rs10494071 combined P value = 8.4 x 10-4). The allele association combined with gene exp, We wish to thank all study participants and their clinicians for their valuable contributions. This work was supported by grants from the Eugenio Rodriguez Pascual Foundation (2012, to MAP), the Government of Catalonia (2009-SGR283, to AV and MAP), the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (R01 DK015556, to JAK), the Red Cooperative Research Thematic Network on Cancer (RTICC) (12/0036/0002 to XRB and 12/0036/0008 to XRB and MAP) and the Spanish Ministry of Health, Fund for Health Research-Institute of Health Carlos III (11/00951 to AU and 12/01528 to MAP).

Published
2014
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11. VAV3 mediates resistance to breast cancer endocrine therapy

Author

Aguilar, Helena, primary, Urruticoechea, Ander, additional, Halonen, Pasi, additional, Kiyotani, Kazuma, additional, Mushiroda, Taisei, additional, Barril, Xavier, additional, Serra-Musach, Jordi, additional, Islam, Abul, additional, Caizzi, Livia, additional, Di Croce, Luciano, additional, Nevedomskaya, Ekaterina, additional, Zwart, Wilbert, additional, Bostner, Josefine, additional, Karlsson, Elin, additional, Pérez Tenorio, Gizeh, additional, Fornander, Tommy, additional, Sgroi, Dennis C, additional, Garcia-Mata, Rafael, additional, Jansen, Maurice PHM, additional, García, Nadia, additional, Bonifaci, Núria, additional, Climent, Fina, additional, Soler, María Teresa, additional, Rodríguez-Vida, Alejo, additional, Gil, Miguel, additional, Brunet, Joan, additional, Martrat, Griselda, additional, Gómez-Baldó, Laia, additional, Extremera, Ana I, additional, Figueras, Agnes, additional, Balart, Josep, additional, Clarke, Robert, additional, Burnstein, Kerry L, additional, Carlson, Kathryn E, additional, Katzenellenbogen, John A, additional, Vizoso, Miguel, additional, Esteller, Manel, additional, Villanueva, Alberto, additional, Rodríguez-Peña, Ana B, additional, Bustelo, Xosé R, additional, Nakamura, Yusuke, additional, Zembutsu, Hitoshi, additional, Stål, Olle, additional, Beijersbergen, Roderick L, additional, and Pujana, Miguel Angel, additional

Published
2014
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12. Centmitor-1, a Novel Acridinyl-Acetohydrazide, Possesses Similar Molecular Interaction Field and Antimitotic Cellular Phenotype as Rigosertib, ON 01910.Na

Author

Mäki-Jouppila, Jenni H.E., primary, Laine, Leena J., additional, Rehnberg, Jonathan, additional, Narvi, Elli, additional, Tiikkainen, Pekka, additional, Hukasova, Elvira, additional, Halonen, Pasi, additional, Lindqvist, Arne, additional, Kallio, Lila, additional, Poso, Antti, additional, and Kallio, Marko J., additional

Published
2014
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13. Intrinsic Resistance to MEK Inhibition in KRAS Mutant Lung and Colon Cancer through Transcriptional Induction of ERBB3

Author

Sun, Chong, primary, Hobor, Sebastijan, additional, Bertotti, Andrea, additional, Zecchin, Davide, additional, Huang, Sidong, additional, Galimi, Francesco, additional, Cottino, Francesca, additional, Prahallad, Anirudh, additional, Grernrum, Wipawadee, additional, Tzani, Anna, additional, Schlicker, Andreas, additional, Wessels, Lodewyk F.A., additional, Smit, Egbert F., additional, Thunnissen, Erik, additional, Halonen, Pasi, additional, Lieftink, Cor, additional, Beijersbergen, Roderick L., additional, Di Nicolantonio, Federica, additional, Bardelli, Alberto, additional, Trusolino, Livio, additional, and Bernards, Rene, additional

Published
2014
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17. Intrinsic Resistance to MEK Inhibition in KRASMutant Lung and Colon Cancer through Transcriptional Induction of ERBB3

Author

Sun, Chong, Hobor, Sebastijan, Bertotti, Andrea, Zecchin, Davide, Huang, Sidong, Galimi, Francesco, Cottino, Francesca, Prahallad, Anirudh, Grernrum, Wipawadee, Tzani, Anna, Schlicker, Andreas, Wessels, Lodewyk F.A., Smit, Egbert F., Thunnissen, Erik, Halonen, Pasi, Lieftink, Cor, Beijersbergen, Roderick L., Di Nicolantonio, Federica, Bardelli, Alberto, Trusolino, Livio, and Bernards, Rene

Abstract

There are no effective therapies for the ∼30% of human malignancies with mutant RASoncogenes. Using a kinome-centered synthetic lethality screen, we find that suppression of the ERBB3receptor tyrosine kinase sensitizes KRASmutant lung and colon cancer cells to MEK inhibitors. We show that MEK inhibition results in MYC-dependent transcriptional upregulation of ERBB3,which is responsible for intrinsic drug resistance. Drugs targeting both EGFR and ERBB2, each capable of forming heterodimers with ERBB3, can reverse unresponsiveness to MEK inhibition by decreasing inhibitory phosphorylation of the proapoptotic proteins BAD and BIM. Moreover, ERBB3 protein level is a biomarker of response to combinatorial treatment. These data suggest a combination strategy for treating KRASmutant colon and lung cancers and a way to identify the tumors that are most likely to benefit from such combinatorial treatment.

Published
2014
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