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 Detalle_Publicacion

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

Abstract: 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.

Otras publicaciones de la misma revista o congreso con autores/as de la Universidad de Cantabria

 Fuente: Oncotarget. 2018 Jul 20;9(56):30869-30882

Editorial: Impact Journals

 Año de publicación: 2018

Nº de páginas: 14

Tipo de publicación: Artículo de Revista

 DOI: 10.18632/oncotarget.25766

ISSN: 1949-2553

Url de la publicación: https://dx.doi.org/10.18632/oncotarget.25766

Autores/as

SUSANA LLERENA SANTIAGO

NURIA GARCIA DIAZ

SORAYA CURIEL DEL OLMO

ANTONIO MANUEL AGRAZ DOBLAS

AGUSTIN GARCIA BLANCO

HELENA PISONERO FRAGA

ALMARAZ, CARMEN

CERECEDA, LAURA

MARTÍNEZ, NEREA

PUENTE, ÁNGELA

LUIS MARTIN RAMOS

CARLOS RODRIGUEZ DE LOPE MARTIN

FEDERICO JOSE CASTILLO SUESCUN

CARMEN CAGIGAS FERNANDEZ

ISIDRO, PABLO

CARLOS RODRIGUEZ DE LOPE LOPEZ

PIRIS, MIGUEL ÁNGEL