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

Irati Garmendia¹  MariaAna Hermosilla¹  M.Ángeles Villaronga¹  Eva Allonca¹  JuanaM. García-Pedrero¹  LuisM. Montuenga¹  Nagore del-Río-Ibisate¹  JuanP. Rodrigo²  Francisco Morís²  Jackeline Agorreta³  Francisco Hermida-Prado³  Patricia Oro³  Rocío Fuente³  René Rodríguez³  Rocío Granda-Díaz³  Laura Santos³  Juan Tornín⁴  Jhudit Perez-Escuredo⁴ 

[1] Instituto Universitario de Oncología del Principado de Asturias, University of Oviedo, 33011 Oviedo, Spain;Ciber de Cáncer, CIBERONC, 28029 Madrid, Spain;Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria del Principado de Asturias;EntreChem SL, Vivero Ciencias de la Salud, 33011 Oviedo, Spain;

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

DOI  :  10.3390/jcm8081157

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown