Applied diagnostics in liver cancer. Efficient combinations of sorafenib with targeted inhibitors blocking AKT/mTOR

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. There is increasing interest in developing specific markers to serve as predictors of response to sorafenib and to guide targeted therapy. Using a sequencing platform designed to study somatic mutations...

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Detalles Bibliográficos
Autores: Llerena Santiago, Susana, García Díaz, Nuria, Curiel Del Olmo, Soraya, Agraz Doblas, Antonio Manuel, García Blanco, Agustín, Pisonero Fraga, Helena, Varela, María, Santibáñez Margüello, Miguel|||0000-0003-2634-615X, Almaraz, Carmen, Cereceda, Laura, Martínez, Nerea, Arias Loste, María Teresa, Puente, Ángela, Martín Ramos, Luis, Rodríguez de Lope López, Carlos, Castillo Suescun, Federico José, Cagigas Fernández, Carmen|||0000-0002-1675-5120, Isidro, Pablo, López López, Carlos|||0000-0002-8901-741X, López Hoyos, Marcos, Llorca Díaz, Francisco Javier|||0000-0001-8569-861X, Agüero Balbín, Jesús, Crespo Facorro, Benedicto|||0000-0001-9709-1276, Varela Egocheaga, Ignacio|||0000-0002-0969-506X, Piris, Miguel Ángel, Crespo García, Javier, Vaqué Díez, José Pedro|||0000-0002-3913-2495
Tipo de recurso: artículo
Fecha de publicación:2018
País:España
Institución:Universidad de Cantabria (UC)
Repositorio:UCrea Repositorio Abierto de la Universidad de Cantabria
Idioma:inglés
OAI Identifier:oai:repositorio.unican.es:10902/15278
Acceso en línea:http://hdl.handle.net/10902/15278
Access Level:acceso abierto
Palabra clave:Hepatocellular Carcinoma
Mutations
Sorafenib
Targeted Therapy
AKT/mTOR
Descripción
Sumario:Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. There is increasing interest in developing specific markers to serve as predictors of response to sorafenib and to guide targeted therapy. Using a sequencing platform designed to study somatic mutations in a selection of 112 genes (HepatoExome), we aimed to characterize lesions from HCC patients and cell lines, and to use the data to study the biological and mechanistic effects of case-specific targeted therapies used alone or in combination with sorafenib. We characterized 331 HCC cases in silico and 32 paired samples obtained prospectively from primary tumors of HCC patients. Each case was analyzed in a time compatible with the requirements of the clinic (within 15 days). In 53% of the discovery cohort cases, we detected unique mutational signatures, with up to 34% of them carrying mutated genes with the potential to guide therapy. In a panel of HCC cell lines, each characterized by a specific mutational signature, sorafenib elicited heterogeneous mechanistic and biological responses, whereas targeted therapy provoked the robust inhibition of cell proliferation and DNA synthesis along with the blockage of AKT/mTOR signaling. The combination of sorafenib with targeted therapies exhibited synergistic anti-HCC biological activity concomitantly with highly effective inhibition of MAPK and AKT/mTOR signaling. Thus, somatic mutations may lead to identify case-specific mechanisms of disease in HCC lesions arising from multiple etiologies. Moreover, targeted therapies guided by molecular characterization, used alone or in combination with sorafenib, can effectively block important HCC disease mechanisms.

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