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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.
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
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SUSANA LLERENA SANTIAGO
NURIA GARCIA DIAZ
SORAYA CURIEL DEL OLMO
ANTONIO MANUEL AGRAZ DOBLAS
AGUSTIN GARCIA BLANCO
HELENA PISONERO FRAGA
VARELA, MARÍA
MIGUEL SANTIBAÑEZ MARGÜELLO
ALMARAZ, CARMEN
CERECEDA, LAURA
MARTÍNEZ, NEREA
MARIA TERESA ARIAS LOSTE
PUENTE, ÁNGELA
LUIS MARTIN RAMOS
CARLOS RODRIGUEZ DE LOPE MARTIN
FEDERICO JOSE CASTILLO SUESCUN
CARMEN CAGIGAS FERNANDEZ
ISIDRO, PABLO
CARLOS RODRIGUEZ DE LOPE LOPEZ
MARCOS LOPEZ HOYOS
FRANCISCO JAVIER LLORCA DIAZ
JESUS AGÜERO BALBIN
BENEDICTO CRESPO FACORRO
IGNACIO VARELA EGOCHEAGA
PIRIS, MIGUEL ÁNGEL
JAVIER CRESPO GARCIA
JOSE PEDRO VAQUE DIEZ
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