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1. Additional file 3 of Correction to: Focal adhesion kinase inhibitor TAE226 combined with Sorafenib slows down hepatocellular carcinoma by multiple epigenetic effects

Author

Romito, Ilaria, Porru, Manuela, Braghini, Maria Rita, Pompili, Luca, Panera, Nadia, Crudele, Annalisa, Gnani, Daniela, De Stefanis, Cristiano, Scarsella, Marco, Pomella, Silvia, Mortera, Stefano Levi, de Billy, Emmanuel, Conti, Adrian Libenzio, Marzano, Valeria, Putignani, Lorenza, Vinciguerra, Manlio, Balsano, Clara, Pastore, Anna, Rota, Rossella, Tartaglia, Marco, Leonetti, Carlo, and Alisi, Anna

Subjects
Data_FILES
Abstract

Additional file 8.

Published
2022
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2. sj-docx-1-tam-10.1177_17588359221113693 – Supplemental material for Targeted therapy for pediatric diffuse intrinsic pontine glioma: a single-center experience

Author

Del Baldo, Giada, Carai, Andrea, Abbas, Rachid, Cacchione, Antonella, Vinci, Mara, Di Ruscio, Valentina, Colafati, Giovanna Stefania, Rossi, Sabrina, Diomedi Camassei, Francesca, Maestro, Nicola, Temelso, Sara, Pericoli, Giulia, De Billy, Emmanuel, Giovannoni, Isabella, Carboni, Alessia, Rinelli, Martina, Agolini, Emanuele, Mackay, Alan, Jones, Chris, Chiesa, Silvia, Balducci, Mario, Locatelli, Franco, and Mastronuzzi, Angela

Subjects
110203 Respiratory Diseases, FOS: Clinical medicine, 111702 Aged Health Care, FOS: Health sciences, 111599 Pharmacology and Pharmaceutical Sciences not elsewhere classified, 111299 Oncology and Carcinogenesis not elsewhere classified
Abstract

Supplemental material, sj-docx-1-tam-10.1177_17588359221113693 for Targeted therapy for pediatric diffuse intrinsic pontine glioma: a single-center experience by Giada Del Baldo, Andrea Carai, Rachid Abbas, Antonella Cacchione, Mara Vinci, Valentina Di Ruscio, Giovanna Stefania Colafati, Sabrina Rossi, Francesca Diomedi Camassei, Nicola Maestro, Sara Temelso, Giulia Pericoli, Emmanuel De Billy, Isabella Giovannoni, Alessia Carboni, Martina Rinelli, Emanuele Agolini, Alan Mackay, Chris Jones, Silvia Chiesa, Mario Balducci, Franco Locatelli and Angela Mastronuzzi in Therapeutic Advances in Medical Oncology

Published
2022
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3. Additional file 2 of Correction to: Focal adhesion kinase inhibitor TAE226 combined with Sorafenib slows down hepatocellular carcinoma by multiple epigenetic effects

Author

Romito, Ilaria, Porru, Manuela, Braghini, Maria Rita, Pompili, Luca, Panera, Nadia, Crudele, Annalisa, Gnani, Daniela, De Stefanis, Cristiano, Scarsella, Marco, Pomella, Silvia, Mortera, Stefano Levi, de Billy, Emmanuel, Conti, Adrian Libenzio, Marzano, Valeria, Putignani, Lorenza, Vinciguerra, Manlio, Balsano, Clara, Pastore, Anna, Rota, Rossella, Tartaglia, Marco, Leonetti, Carlo, and Alisi, Anna

Subjects
Data_FILES
Abstract

Additional file 7.

Published
2022
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4. Additional file 1 of Correction to: Focal adhesion kinase inhibitor TAE226 combined with Sorafenib slows down hepatocellular carcinoma by multiple epigenetic effects

Author

Romito, Ilaria, Porru, Manuela, Braghini, Maria Rita, Pompili, Luca, Panera, Nadia, Crudele, Annalisa, Gnani, Daniela, De Stefanis, Cristiano, Scarsella, Marco, Pomella, Silvia, Mortera, Stefano Levi, de Billy, Emmanuel, Conti, Adrian Libenzio, Marzano, Valeria, Putignani, Lorenza, Vinciguerra, Manlio, Balsano, Clara, Pastore, Anna, Rota, Rossella, Tartaglia, Marco, Leonetti, Carlo, and Alisi, Anna

Subjects
Data_FILES
Abstract

Additional file 6.

Published
2022
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5. sj-docx-2-tam-10.1177_17588359221113693 – Supplemental material for Targeted therapy for pediatric diffuse intrinsic pontine glioma: a single-center experience

Author

Del Baldo, Giada, Carai, Andrea, Abbas, Rachid, Cacchione, Antonella, Vinci, Mara, Di Ruscio, Valentina, Colafati, Giovanna Stefania, Rossi, Sabrina, Diomedi Camassei, Francesca, Maestro, Nicola, Temelso, Sara, Pericoli, Giulia, De Billy, Emmanuel, Giovannoni, Isabella, Carboni, Alessia, Rinelli, Martina, Agolini, Emanuele, Mackay, Alan, Jones, Chris, Chiesa, Silvia, Balducci, Mario, Locatelli, Franco, and Mastronuzzi, Angela

Subjects
110203 Respiratory Diseases, FOS: Clinical medicine, 111702 Aged Health Care, FOS: Health sciences, 111599 Pharmacology and Pharmaceutical Sciences not elsewhere classified, 111299 Oncology and Carcinogenesis not elsewhere classified
Abstract

Supplemental material, sj-docx-2-tam-10.1177_17588359221113693 for Targeted therapy for pediatric diffuse intrinsic pontine glioma: a single-center experience by Giada Del Baldo, Andrea Carai, Rachid Abbas, Antonella Cacchione, Mara Vinci, Valentina Di Ruscio, Giovanna Stefania Colafati, Sabrina Rossi, Francesca Diomedi Camassei, Nicola Maestro, Sara Temelso, Giulia Pericoli, Emmanuel De Billy, Isabella Giovannoni, Alessia Carboni, Martina Rinelli, Emanuele Agolini, Alan Mackay, Chris Jones, Silvia Chiesa, Mario Balducci, Franco Locatelli and Angela Mastronuzzi in Therapeutic Advances in Medical Oncology

Published
2022
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6. sj-docx-2-tam-10.1177_17588359221113693 – Supplemental material for Targeted therapy for pediatric diffuse intrinsic pontine glioma: a single-center experience

Author

Del Baldo, Giada, Carai, Andrea, Abbas, Rachid, Cacchione, Antonella, Vinci, Mara, Di Ruscio, Valentina, Colafati, Giovanna Stefania, Rossi, Sabrina, Diomedi Camassei, Francesca, Maestro, Nicola, Temelso, Sara, Pericoli, Giulia, De Billy, Emmanuel, Giovannoni, Isabella, Carboni, Alessia, Rinelli, Martina, Agolini, Emanuele, Mackay, Alan, Jones, Chris, Chiesa, Silvia, Balducci, Mario, Locatelli, Franco, and Mastronuzzi, Angela

Subjects
110203 Respiratory Diseases, FOS: Clinical medicine, 111702 Aged Health Care, FOS: Health sciences, 111599 Pharmacology and Pharmaceutical Sciences not elsewhere classified, 111299 Oncology and Carcinogenesis not elsewhere classified
Abstract

Supplemental material, sj-docx-2-tam-10.1177_17588359221113693 for Targeted therapy for pediatric diffuse intrinsic pontine glioma: a single-center experience by Giada Del Baldo, Andrea Carai, Rachid Abbas, Antonella Cacchione, Mara Vinci, Valentina Di Ruscio, Giovanna Stefania Colafati, Sabrina Rossi, Francesca Diomedi Camassei, Nicola Maestro, Sara Temelso, Giulia Pericoli, Emmanuel De Billy, Isabella Giovannoni, Alessia Carboni, Martina Rinelli, Emanuele Agolini, Alan Mackay, Chris Jones, Silvia Chiesa, Mario Balducci, Franco Locatelli and Angela Mastronuzzi in Therapeutic Advances in Medical Oncology

Published
2022
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7. sj-docx-1-tam-10.1177_17588359221113693 – Supplemental material for Targeted therapy for pediatric diffuse intrinsic pontine glioma: a single-center experience

Author

Del Baldo, Giada, Carai, Andrea, Abbas, Rachid, Cacchione, Antonella, Vinci, Mara, Di Ruscio, Valentina, Colafati, Giovanna Stefania, Rossi, Sabrina, Diomedi Camassei, Francesca, Maestro, Nicola, Temelso, Sara, Pericoli, Giulia, De Billy, Emmanuel, Giovannoni, Isabella, Carboni, Alessia, Rinelli, Martina, Agolini, Emanuele, Mackay, Alan, Jones, Chris, Chiesa, Silvia, Balducci, Mario, Locatelli, Franco, and Mastronuzzi, Angela

Subjects
110203 Respiratory Diseases, FOS: Clinical medicine, 111702 Aged Health Care, FOS: Health sciences, 111599 Pharmacology and Pharmaceutical Sciences not elsewhere classified, 111299 Oncology and Carcinogenesis not elsewhere classified
Abstract

Supplemental material, sj-docx-1-tam-10.1177_17588359221113693 for Targeted therapy for pediatric diffuse intrinsic pontine glioma: a single-center experience by Giada Del Baldo, Andrea Carai, Rachid Abbas, Antonella Cacchione, Mara Vinci, Valentina Di Ruscio, Giovanna Stefania Colafati, Sabrina Rossi, Francesca Diomedi Camassei, Nicola Maestro, Sara Temelso, Giulia Pericoli, Emmanuel De Billy, Isabella Giovannoni, Alessia Carboni, Martina Rinelli, Emanuele Agolini, Alan Mackay, Chris Jones, Silvia Chiesa, Mario Balducci, Franco Locatelli and Angela Mastronuzzi in Therapeutic Advances in Medical Oncology

Published
2022
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8. Additional file 7 of Focal adhesion kinase inhibitor TAE226 combined with Sorafenib slows down hepatocellular carcinoma by multiple epigenetic effects

Author

Romito, Ilaria, Porru, Manuela, Braghini, Maria Rita, Pompili, Luca, Panera, Nadia, Crudele, Annalisa, Gnani, Daniela, De Stefanis, Cristiano, Scarsella, Marco, Pomella, Silvia, Levi Mortera, Stefano, de Billy, Emmanuel, Conti, Adrian Libenzio, Marzano, Valeria, Putignani, Lorenza, Vinciguerra, Manlio, Balsano, Clara, Pastore, Anna, Rota, Rossella, Tartaglia, Marco, Leonetti, Carlo, and Alisi, Anna

Subjects
digestive system diseases
Abstract

Additional file 7: Figure S2. Evaluation of the IC50 values of TAE226 and SOR on HCC cell viability after 2 and 5 days. Cell viability, measured by XTT assay, after 2 and 5 days from treatment with TAE226 or SOR, in HepG2 and Huh7 cells. Values are the mean OD �� SD of three independent experiments repeated at least in duplicate. Data were analysed by ANOVA. ***p

Published
2021
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9. Additional file 6 of Focal adhesion kinase inhibitor TAE226 combined with Sorafenib slows down hepatocellular carcinoma by multiple epigenetic effects

Author

Romito, Ilaria, Porru, Manuela, Braghini, Maria Rita, Pompili, Luca, Panera, Nadia, Crudele, Annalisa, Gnani, Daniela, De Stefanis, Cristiano, Scarsella, Marco, Pomella, Silvia, Levi Mortera, Stefano, de Billy, Emmanuel, Conti, Adrian Libenzio, Marzano, Valeria, Putignani, Lorenza, Vinciguerra, Manlio, Balsano, Clara, Pastore, Anna, Rota, Rossella, Tartaglia, Marco, Leonetti, Carlo, and Alisi, Anna

Subjects
digestive system diseases
Abstract

Additional file 6: Figure S1. FAK phosphorylation in HCC cells after IC50 values of treatments. Quantitative analysis of pTyr397FAK expression after 48 h of treatment with the different drugs, in HepG2 and Huh7 cells. Values are the mean arbitrary units �� SD of at least three independent experiments. Data were analysed by 2-tailed Student���s t test. *p

Published
2021
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10. Additional file 10 of Focal adhesion kinase inhibitor TAE226 combined with Sorafenib slows down hepatocellular carcinoma by multiple epigenetic effects

Author

Romito, Ilaria, Porru, Manuela, Braghini, Maria Rita, Pompili, Luca, Panera, Nadia, Crudele, Annalisa, Gnani, Daniela, De Stefanis, Cristiano, Scarsella, Marco, Pomella, Silvia, Levi Mortera, Stefano, de Billy, Emmanuel, Conti, Adrian Libenzio, Marzano, Valeria, Putignani, Lorenza, Vinciguerra, Manlio, Balsano, Clara, Pastore, Anna, Rota, Rossella, Tartaglia, Marco, Leonetti, Carlo, and Alisi, Anna

Abstract

Additional file 10: Figure S5. Analysis of FAK nuclear interaction with specific epigenetics regulators. (A) Coomassie-stained 1D SDS-PAGE gels used for the in-gel digestions of nuclear immunoprecipitates of FAK in HCC cells. The photographs showed gel lanes excision into 10 bands for mass spectrometry characterization of FAK nuclear interactors. (B) Pipeline employed for the analysis of proteomics data.

Published
2021
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11. Additional file 2 of Focal adhesion kinase inhibitor TAE226 combined with Sorafenib slows down hepatocellular carcinoma by multiple epigenetic effects

Author

Romito, Ilaria, Porru, Manuela, Braghini, Maria Rita, Pompili, Luca, Panera, Nadia, Crudele, Annalisa, Gnani, Daniela, De Stefanis, Cristiano, Scarsella, Marco, Pomella, Silvia, Levi Mortera, Stefano, de Billy, Emmanuel, Conti, Adrian Libenzio, Marzano, Valeria, Putignani, Lorenza, Vinciguerra, Manlio, Balsano, Clara, Pastore, Anna, Rota, Rossella, Tartaglia, Marco, Leonetti, Carlo, and Alisi, Anna

Abstract

Additional file 2: Table S2. In vivo antitumor efficacy of TAE226>SOR combination on orthotopic liver tumour.

Published
2021
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12. Additional file 9 of Focal adhesion kinase inhibitor TAE226 combined with Sorafenib slows down hepatocellular carcinoma by multiple epigenetic effects

Author

Romito, Ilaria, Porru, Manuela, Braghini, Maria Rita, Pompili, Luca, Panera, Nadia, Crudele, Annalisa, Gnani, Daniela, De Stefanis, Cristiano, Scarsella, Marco, Pomella, Silvia, Levi Mortera, Stefano, de Billy, Emmanuel, Conti, Adrian Libenzio, Marzano, Valeria, Putignani, Lorenza, Vinciguerra, Manlio, Balsano, Clara, Pastore, Anna, Rota, Rossella, Tartaglia, Marco, Leonetti, Carlo, and Alisi, Anna

Abstract

Additional file 9: Figure S4. Pilot study for quantitative setting of TAE226 concentration in a heterotopic HepG2 xenograft model of HCC. (A) Quantitative analysis of tumour weight at various time points in NT animals or after TAE226 treatments. P values were calculated at day 12 using an unpaired two-tailed t-test, between treated and untreated tumours. **** p

Published
2021
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13. Additional file 1 of Focal adhesion kinase inhibitor TAE226 combined with Sorafenib slows down hepatocellular carcinoma by multiple epigenetic effects

Author

Romito, Ilaria, Porru, Manuela, Braghini, Maria Rita, Pompili, Luca, Panera, Nadia, Crudele, Annalisa, Gnani, Daniela, De Stefanis, Cristiano, Scarsella, Marco, Pomella, Silvia, Levi Mortera, Stefano, de Billy, Emmanuel, Conti, Adrian Libenzio, Marzano, Valeria, Putignani, Lorenza, Vinciguerra, Manlio, Balsano, Clara, Pastore, Anna, Rota, Rossella, Tartaglia, Marco, Leonetti, Carlo, and Alisi, Anna

Abstract

Additional file 1: Table S1. List of antibodies.

Published
2021
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14. Additional file 11 of Focal adhesion kinase inhibitor TAE226 combined with Sorafenib slows down hepatocellular carcinoma by multiple epigenetic effects

Author

Romito, Ilaria, Porru, Manuela, Braghini, Maria Rita, Pompili, Luca, Panera, Nadia, Crudele, Annalisa, Gnani, Daniela, De Stefanis, Cristiano, Scarsella, Marco, Pomella, Silvia, Levi Mortera, Stefano, de Billy, Emmanuel, Conti, Adrian Libenzio, Marzano, Valeria, Putignani, Lorenza, Vinciguerra, Manlio, Balsano, Clara, Pastore, Anna, Rota, Rossella, Tartaglia, Marco, Leonetti, Carlo, and Alisi, Anna

Abstract

Additional file 11: Figure S6. pTyr397FAK nuclear interactors before and after treatment with TAE226 > SOR. Representative images of immunofluorescence for pTyr397FAK, ��-Catenin, HDAC1 and HDAC2 in HepG2 and Huh7 cells NT and after TAE226 > SOR treatment. 60X Magnification.

Published
2021
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15. Additional file 3 of Focal adhesion kinase inhibitor TAE226 combined with Sorafenib slows down hepatocellular carcinoma by multiple epigenetic effects

Author

Romito, Ilaria, Porru, Manuela, Braghini, Maria Rita, Pompili, Luca, Panera, Nadia, Crudele, Annalisa, Gnani, Daniela, De Stefanis, Cristiano, Scarsella, Marco, Pomella, Silvia, Levi Mortera, Stefano, de Billy, Emmanuel, Conti, Adrian Libenzio, Marzano, Valeria, Putignani, Lorenza, Vinciguerra, Manlio, Balsano, Clara, Pastore, Anna, Rota, Rossella, Tartaglia, Marco, Leonetti, Carlo, and Alisi, Anna

Abstract

Additional file 3: Table S3. Common up- and down-regulated genes.

Published
2021
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16. Additional file 5 of Focal adhesion kinase inhibitor TAE226 combined with Sorafenib slows down hepatocellular carcinoma by multiple epigenetic effects

Author

Romito, Ilaria, Porru, Manuela, Braghini, Maria Rita, Pompili, Luca, Panera, Nadia, Crudele, Annalisa, Gnani, Daniela, De Stefanis, Cristiano, Scarsella, Marco, Pomella, Silvia, Levi Mortera, Stefano, de Billy, Emmanuel, Conti, Adrian Libenzio, Marzano, Valeria, Putignani, Lorenza, Vinciguerra, Manlio, Balsano, Clara, Pastore, Anna, Rota, Rossella, Tartaglia, Marco, Leonetti, Carlo, and Alisi, Anna

Subjects
Data_FILES
Abstract

Additional file 5: Table S5. GO annotations.

Published
2021
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17. Additional file 8 of Focal adhesion kinase inhibitor TAE226 combined with Sorafenib slows down hepatocellular carcinoma by multiple epigenetic effects

Author

Romito, Ilaria, Porru, Manuela, Braghini, Maria Rita, Pompili, Luca, Panera, Nadia, Crudele, Annalisa, Gnani, Daniela, De Stefanis, Cristiano, Scarsella, Marco, Pomella, Silvia, Levi Mortera, Stefano, de Billy, Emmanuel, Conti, Adrian Libenzio, Marzano, Valeria, Putignani, Lorenza, Vinciguerra, Manlio, Balsano, Clara, Pastore, Anna, Rota, Rossella, Tartaglia, Marco, Leonetti, Carlo, and Alisi, Anna

Abstract

Additional file 8: Figure S3. IGF-1R in HCC cells after treatment with TAE226 > SOR compared to single treatments. Representative immunoblot and quantitative analysis of phosphorylated IGF-1R after 48 h from treatment with the different drugs, in HepG2 (A) and Huh7 cells (B). ��Tubulin served as loading control. Values are the mean arbitrary units �� SD of at least three independent experiments. Data were analysed by 2-tailed Student���s t test. **p

Published
2021
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18. Discovery of a Chemical Probe Bisamide (CCT251236): An Orally Bioavailable Efficacious Pirin Ligand from a Heat Shock Transcription Factor 1 (HSF1) Phenotypic Screen

Author

Cheeseman, Matthew D., Chessum, Nicola E. A., Rye, Carl S., Pasqua, A. Elisa, Tucker, Michael J., Wilding, Birgit, Evans, Lindsay E., Lepri, Susan, Richards, Meirion, Sharp, Swee Y., Ali, Salyha, Rowlands, Martin, O’Fee, Lisa, Miah, Asadh, Hayes, Angela, Henley, Alan T., Powers, Marissa, te Poele, Robert, De Billy, Emmanuel, Pellegrino, Loredana, Raynaud, Florence, Burke, Rosemary, van Montfort, Rob L. M., Eccles, Suzanne A., Workman, Paul, and Jones, Keith

Subjects
Spectrometry, Mass, Electrospray Ionization, Proton Magnetic Resonance Spectroscopy, Administration, Oral, Biological Availability, Nuclear Proteins, Ligands, Amides, Article, Dioxygenases, DNA-Binding Proteins, Heat Shock Transcription Factors, Drug Discovery, Quinolines, Carbon-13 Magnetic Resonance Spectroscopy, Carrier Proteins, Transcription Factors
Abstract

Phenotypic screens, which focus on measuring and quantifying discrete cellular changes rather than affinity for individual recombinant proteins, have recently attracted renewed interest as an efficient strategy for drug discovery. In this article, we describe the discovery of a new chemical probe, bisamide (CCT251236), identified using an unbiased phenotypic screen to detect inhibitors of the HSF1 stress pathway. The chemical probe is orally bioavailable and displays efficacy in a human ovarian carcinoma xenograft model. By developing cell-based SAR and using chemical proteomics, we identified pirin as a high affinity molecular target, which was confirmed by SPR and crystallography.

Published
2016

20. MET inhibition sensitizes rhabdomyosarcoma cells to NOTCH signaling suppression

Author

Clara Perrone, Silvia Pomella, Matteo Cassandri, Michele Pezzella, Giuseppe Maria Milano, Marta Colletti, Cristina Cossetti, Giulia Pericoli, Angela Di Giannatale, Emmanuel de Billy, Maria Vinci, Stefania Petrini, Francesco Marampon, Concetta Quintarelli, Riccardo Taulli, Josep Roma, Soledad Gallego, Simona Camero, Paolo Mariottini, Manuela Cervelli, Roberta Maestro, Lucio Miele, Biagio De Angelis, Franco Locatelli, Rossella Rota, Institut Català de la Salut, [Perrone C] Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy. Department of Science, 'Department of Excellence 2018-2022', University of Rome 'Roma Tre', Rome, Italy. [Pomella S, Pezzella M, Milano GM, Colletti M] Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy. [Cassandri M] Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy. Department of Radiotherapy, Sapienza University, Rome, Italy. [Roma J, Gallego S] Grup de Recerca Translacional en Càncer en la Infància i l’Adolescència, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain, Vall d'Hebron Barcelona Hospital Campus, Perrone, Clara, Pomella, Silvia, Cassandri, Matteo, Pezzella, Michele, Milano, Giuseppe Maria, Colletti, Marta, Cossetti, Cristina, Pericoli, Giulia, Di Giannatale, Angela, de Billy, Emmanuel, Vinci, Maria, Petrini, Stefania, Marampon, Francesco, Quintarelli, Concetta, Taulli, Riccardo, Roma, Josep, Gallego, Soledad, Camero, Simona, Mariottini, Paolo, Cervelli, Manuela, Maestro, Roberta, Miele, Lucio, De Angelis, Biagio, Locatelli, Franco, and Rota, Rossella

Subjects
Cancer Research, Pediatria, drug resistance, MET, NOTCH signaling, combination therapy, rhabdomyosarcoma, soft tissue sarcoma, targeted therapy, γ-secretase, acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticos::inhibidores de proteínas cinasas [COMPUESTOS QUÍMICOS Y DROGAS], Health Occupations::Medicine::Pediatrics [DISCIPLINES AND OCCUPATIONS], Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Other subheadings::Other subheadings::/drug therapy [Other subheadings], neoplasias::neoplasias por tipo histológico::neoplasias de tejido conjuntivo y de tejidos blandos::neoplasias de tejido muscular::miosarcoma::rabdomiosarcoma [ENFERMEDADES], Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors::Protein Kinase Inhibitors [CHEMICALS AND DRUGS], Settore MED/05, Tumors de parts toves - Tractament, Proteïnes quinases - Inhibidors, Oncology, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Neoplasms::Neoplasms by Histologic Type::Neoplasms, Connective and Soft Tissue::Neoplasms, Muscle Tissue::Myosarcoma::Rhabdomyosarcoma [DISEASES], profesiones sanitarias::medicina::pediatría [DISCIPLINAS Y OCUPACIONES]
Abstract

Drug resistance; Soft tissue sarcoma; Targeted therapy Resistencia a las drogas; Sarcoma de tejido blando; Terapia dirigida Resistència als fàrmacs; Sarcoma dels teixits tous; Teràpia dirigida Rhabdomyosarcoma (RMS) is a pediatric myogenic soft tissue sarcoma. The Fusion-Positive (FP) subtype expresses the chimeric protein PAX3-FOXO1 (P3F) while the Fusion-Negative (FN) is devoid of any gene translocation. FP-RMS and metastatic FN-RMS are often unresponsive to conventional therapy. Therefore, novel therapeutic approaches are needed to halt tumor progression. NOTCH signaling has oncogenic functions in RMS and its pharmacologic inhibition through γ-secretase inhibitors blocks tumor growth in vitro and in vivo. Here, we show that NOTCH signaling blockade resulted in the up-regulation and phosphorylation of the MET oncogene in both RH30 (FP-RMS) and RD (FN-RMS) cell lines. Pharmacologic inhibition of either NOTCH or MET signaling slowed proliferation and restrained cell survival compared to control cells partly by increasing Annexin V and CASP3/7 activation. Co-treatment with NOTCH and MET inhibitors significantly amplified these effects and enhanced PARP1 cleavage in both cell lines. Moreover, it severely hampered cell migration, colony formation, and anchorage-independent growth compared to single-agent treatments in both cell lines and significantly prevented the growth of FN-RMS cells grown as spheroids. Collectively, our results unveil the overexpression of the MET oncogene by NOTCH signaling targeting in RMS cells and show that MET pathway blockade sensitizes them to NOTCH inhibition. This research was funded by Associazione Italiana per la Ricerca sul Cancro (AIRC) #15312 to RR and #24696 to FM; Italian Ministry of Health (Ricerca Corrente) to BDA, CQ, and RR; AIRC 5xmille #9962 to FL; Italian Ministry of Health (Fondi 5xmille 2021-2022) to RR; Alleanza Contro il Cancro (ACC) Italian Network-Working Group Sarcomas to BDA, RM, and RR; Fondi Ateneo 2019 to FM; MIUR-Italy: Grant to Department of Science, Roma Tre University (Dipartimento di Eccellenza, ARTICOLO 1, COMMI 314—337 LEGGE 232/2016) to MCe and PM.

Published
2022

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