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

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Unidad de Investigación, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO), Hospital General Universitario de Elche, 03203 Elche (Alicante), Spain
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Unidad de Investigación, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Hospital General Universitario de Alicante, 03005 Alicante, Spain
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Instituto de Biología Molecular y Celular (IBMC) and Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, 03202 Elche (Alicante), Spain
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Unidad de Genética Molecular, Hospital General Universitario de Elche, 03203 Elche (Alicante), Spain
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Servicio de Oncología, Hospital General Universitario de Elche, 03203 Elche (Alicante), Spain
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Departamento de Fisiología, Genética y Microbiología, Facultad de Ciencias, Universidad de Alicante, 03080 Alicante, Spain
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2020, 12(12), 3717; https://doi.org/10.3390/cancers12123717
Received: 24 November 2020 / Accepted: 9 December 2020 / Published: 11 December 2020
We have tested the effects of IGF-1R tyrosine kinase inhibitors BMS-754807 (BMS) and OSI-906 (OSI) on human colon, pancreatic carcinoma cell, and glioblastoma cell lines and primary cultures. Although OSI and BMS are able to inhibit IGF-1R activity at low doses, the differential effect on cell proliferation and cell-cycle phase distribution shown by both compounds probes that many effects observed are mediated by BMS off-target interactions. Using MAPKs ELISAs and phospho-RTK array analysis, we have identified several BMS regulated putative kinases able to mediate BMS off-target effects. Interestingly, molecular docking assays suggest that BMS could affect these kinases not only by blocking their ATP-binding domain, but also by means of allosteric interactions. Since BMS has an important antineoplastic effect on these poor prognosis types of cancer, these compounds could be taken in consideration for treatment independently of IGF-1R status.
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. View Full-Text
Keywords: IGF-1R inhibitor; ATP-binding domain; off-target inhibition; molecular docking; pancreatic carcinoma; colon carcinoma; glioblastoma; tyrosine kinase IGF-1R inhibitor; ATP-binding domain; off-target inhibition; molecular docking; pancreatic carcinoma; colon carcinoma; glioblastoma; tyrosine kinase
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MDPI and ACS Style

Fuentes-Baile, M.; Ventero, M.P.; Encinar, J.A.; García-Morales, P.; Poveda-Deltell, M.; Pérez-Valenciano, E.; Barberá, V.M.; 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, 3717. https://doi.org/10.3390/cancers12123717

AMA Style

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

Chicago/Turabian Style

Fuentes-Baile, María, María P. Ventero, José A. Encinar, Pilar García-Morales, María Poveda-Deltell, Elizabeth Pérez-Valenciano, Víctor M. Barberá, Javier Gallego-Plazas, Álvaro Rodríguez-Lescure, José Martín-Nieto, and Miguel Saceda. 2020. "Differential Effects of IGF-1R Small Molecule Tyrosine Kinase Inhibitors BMS-754807 and OSI-906 on Human Cancer Cell Lines" Cancers 12, no. 12: 3717. https://doi.org/10.3390/cancers12123717

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