Differential Effects of IGF-1R Small Molecule Tyrosine Kinase Inhibitors BMS-754807 and OSI-906 on Human Cancer Cell Lines

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Title: Differential Effects of IGF-1R Small Molecule Tyrosine Kinase Inhibitors BMS-754807 and OSI-906 on Human Cancer Cell Lines
Authors: Fuentes-Baile, Maria | Ventero, Maria Paz | Encinar, José A. | García-Morales, Pilar | Poveda-Deltell, María | Pérez-Valenciano, Elizabeth | Barberá, Víctor Manuel | Gallego-Plazas, Javier | Rodriguez-Lescure, Alvaro | Martín-Nieto, José | Saceda, Miguel
Research Group/s: Genética Humana y de Mamíferos (GHM) | Transducción de Señales en Bacterias
Center, Department or Service: Universidad de Alicante. Departamento de Fisiología, Genética y Microbiología
Keywords: IGF-1R inhibitor | ATP-binding domain | Off-target inhibition | Molecular docking | Pancreatic carcinoma | Colon carcinoma | Glioblastoma | Tyrosine kinase
Knowledge Area: Genética
Issue Date: 11-Dec-2020
Publisher: MDPI
Citation: Fuentes-Baile M, Ventero MP, Encinar JA, García-Morales P, Poveda-Deltell M, Pérez-Valenciano E, Barberá VM, Gallego-Plazas J, Rodríguez-Lescure Á, Martín-Nieto J, Saceda M. Differential Effects of IGF-1R Small Molecule Tyrosine Kinase Inhibitors BMS-754807 and OSI-906 on Human Cancer Cell Lines. Cancers. 2020; 12(12):3717. https://doi.org/10.3390/cancers12123717
Abstract: We have determined the effects of the IGF-1R tyrosine kinase inhibitors BMS-754807 (BMS) and OSI-906 (OSI) on cell proliferation and cell-cycle phase distribution in human colon, pancreatic carcinoma, and glioblastoma cell lines and primary cultures. IGF-1R signaling was blocked by BMS and OSI at equivalent doses, although both inhibitors exhibited differential antiproliferative effects. In all pancreatic carcinoma cell lines tested, BMS exerted a strong antiproliferative effect, whereas OSI had a minimal effect. Similar results were obtained on glioblastoma primary cultures, where HGUE-GB-15, -16 and -17 displayed resistance to OSI effects, whereas they were inhibited in their proliferation by BMS. Differential effects of BMS and OSI were also observed in colon carcinoma cell lines. Both inhibitors also showed different effects on cell cycle phase distribution, BMS induced G2/M arrest followed by cell death, while OSI induced G1 arrest with no cell death. Both inhibitors also showed different effects on other protein kinases activities. Taken together, our results are indicative that BMS mainly acts through off-target effects exerted on other protein kinases. Given that BMS exhibits a potent antiproliferative effect, we believe that this compound could be useful for the treatment of different types of tumors independently of their IGF-1R activation status.
Sponsor: This research was funded by a Grant from Instituto de Salud Carlos III Grant PI012/02025 co-supported by FEDER funds and PRECIPITA crowdfunding platform from Fundación Española para la Ciencia y la Tecnología (Fecyt) to M. Saceda and AMACMED (Asociación de mujeres afectadas por cáncer de mama de Elche y Comarca) and Monica Moraleda donation to M. Saceda. The Spanish Ministry of Economy and Competitiveness (MINECO, Project RTI2018-096724-B-C21) and the Generalitat Valenciana (PROMETEO/2016/006) supported the work in the Encinar laboratory.
URI: http://hdl.handle.net/10045/110920
ISSN: 2072-6694
DOI: 10.3390/cancers12123717
Language: eng
Type: info:eu-repo/semantics/article
Rights: © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Peer Review: si
Publisher version: https://doi.org/10.3390/cancers12123717
Appears in Collections:INV - TSB - Artículos de Revistas
INV - GHM - Artículos de Revistas

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