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Hermida-Prado F, Villaronga MÁ, Granda-Díaz R, et al. The SRC Inhibitor Dasatinib Induces Stem Cell-Like Properties in Head and Neck Cancer Cells that are Effectively Counteracted by the Mithralog EC-8042. J Clin Med. 2019;8(8)doi: 10.3390/jcm8081157.
Hermida-Prado, F., Villaronga, M. �. �., Granda-Díaz, R., Del-Río-Ibisate, N., Santos, L., Hermosilla, M. A., Oro, P., Allonca, E., Agorreta, J., Garmendia, I., Tornín, J., Perez-Escuredo, J., Fuente, R., Montuenga, L. M., Morís, F., Rodrigo, J. P., Rodríguez, R., & García-Pedrero, J. M. (2019). The SRC Inhibitor Dasatinib Induces Stem Cell-Like Properties in Head and Neck Cancer Cells that are Effectively Counteracted by the Mithralog EC-8042. Journal of clinical medicine, 8(8), . https://doi.org/10.3390/jcm8081157
Hermida-Prado, Francisco, et al. "The SRC Inhibitor Dasatinib Induces Stem Cell-Like Properties in Head and Neck Cancer Cells that are Effectively Counteracted by the Mithralog EC-8042." Journal of clinical medicine vol. 8,8 (2019). doi: https://doi.org/10.3390/jcm8081157
Hermida-Prado F, Villaronga MÁ, Granda-Díaz R, Del-Río-Ibisate N, Santos L, Hermosilla MA, Oro P, Allonca E, Agorreta J, Garmendia I, Tornín J, Perez-Escuredo J, Fuente R, Montuenga LM, Morís F, Rodrigo JP, Rodríguez R, García-Pedrero JM. The SRC Inhibitor Dasatinib Induces Stem Cell-Like Properties in Head and Neck Cancer Cells that are Effectively Counteracted by the Mithralog EC-8042. J Clin Med. 2019 Aug 02;8(8). doi: 10.3390/jcm8081157. PMID: 31382448; PMCID: PMC6722627.
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J Clin Med. 2019 Aug 02;8(8). doi: 10.3390/jcm8081157.

The SRC Inhibitor Dasatinib Induces Stem Cell-Like Properties in Head and Neck Cancer Cells that are Effectively Counteracted by the Mithralog EC-8042.

Journal of clinical medicine

Francisco Hermida-Prado, M Ángeles Villaronga, Rocío Granda-Díaz, Nagore Del-Río-Ibisate, Laura Santos, Maria Ana Hermosilla, Patricia Oro, Eva Allonca, Jackeline Agorreta, Irati Garmendia, Juan Tornín, Jhudit Perez-Escuredo, Rocío Fuente, Luis M Montuenga, Francisco Morís, Juan P Rodrigo, René Rodríguez, Juana M García-Pedrero

Affiliations

  1. Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria del Principado de Asturias; Instituto Universitario de Oncología del Principado de Asturias, University of Oviedo, 33011 Oviedo, Spain.
  2. Ciber de Cáncer, CIBERONC, 28029 Madrid, Spain.
  3. EntreChem SL, Vivero Ciencias de la Salud, 33011 Oviedo, Spain.
  4. Program in Solid Tumors, Center for Applied Medical Research (CIMA), Department of Pathology, Anatomy and Physiology, University of Navarra, and Navarra's Health Research Institute (IDISNA), 31008 Pamplona, Spain.
  5. Division of Pediatrics, Department of Medicine, Faculty of Medicine, University of Oviedo, 33006 Oviedo, Spain.
  6. Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria del Principado de Asturias; Instituto Universitario de Oncología del Principado de Asturias, University of Oviedo, 33011 Oviedo, Spain. [email protected].
  7. Ciber de Cáncer, CIBERONC, 28029 Madrid, Spain. [email protected].
  8. Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria del Principado de Asturias; Instituto Universitario de Oncología del Principado de Asturias, University of Oviedo, 33011 Oviedo, Spain. [email protected].
  9. Ciber de Cáncer, CIBERONC, 28029 Madrid, Spain. [email protected].

PMID: 31382448 PMCID: PMC6722627 DOI: 10.3390/jcm8081157

Abstract

The frequent dysregulation of SRC family kinases (SFK) in multiple cancers prompted various inhibitors to be actively tested in preclinical and clinical trials. Disappointingly, dasatinib and saracatinib failed to demonstrate monotherapeutic efficacy in patients with head and neck squamous cell carcinomas (HNSCC). Deeper functional and mechanistic knowledge of the actions of these drugs is therefore needed to improve clinical outcome and to develop more efficient combinational strategies. Even though the SFK inhibitors dasatinib and saracatinib robustly blocked cell migration and invasion in HNSCC cell lines, this study unveils undesirable stem cell-promoting functions that could explain the lack of clinical efficacy in HNSCC patients. These deleterious effects were targeted by the mithramycin analog EC-8042 that efficiently eliminated cancer stem cells (CSC)-enriched tumorsphere cultures as well as tumor bulk cells and demonstrated potent antitumor activity in vivo. Furthermore, combination treatment of dasatinib with EC-8042 provided favorable complementary anti-proliferative, anti-invasive, and anti-CSC functions without any noticeable adverse interactions of both agents. These findings strongly support combinational strategies with EC-8042 for clinical testing in HNSCC patients. These data may have implications on ongoing dasatinib-based trials.

Keywords: EC-8042; SRC; cancer stem cells; dasatinib; head and neck squamous cell carcinoma; saracatinib

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