Research Papers:

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

Susana Llerena, Nuria García-Díaz, Soraya Curiel-Olmo, Antonio Agraz- Doblas, Agustín García-Blanco, Helena Pisonero, María Varela, Miguel Santibáñez, Carmen Almaraz, Laura Cereceda, Nerea Martínez, María Teresa Arias-Loste, Ángela Puente, Luis Martín-Ramos, Carlos Rodríguez de Lope, Federico Castillo-Suescun, Carmen Cagigas-Fernandez, Pablo Isidro, Carlos Lopez-López, Marcos Lopez-Hoyos, Javier Llorca, Jesús Agüero, Benedicto Crespo-Facorro, Ignacio Varela, Miguel Ángel Piris, Javier Crespo and José Pedro Vaqué _

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Oncotarget. 2018; 9:30869-30882. https://doi.org/10.18632/oncotarget.25766

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Susana Llerena1,2,*, Nuria García-Díaz3,4,*, Soraya Curiel-Olmo3, Antonio Agraz-Doblas4,5, Agustín García-Blanco1,2, Helena Pisonero2,4, María Varela6, Miguel Santibáñez7, Carmen Almaraz3, Laura Cereceda3, Nerea Martínez3, María Teresa Arias-Loste1,2, Ángela Puente1,2, Luis Martín-Ramos1,2, Carlos Rodríguez de Lope1,2, Federico Castillo-Suescun8, Carmen Cagigas-Fernandez8, Pablo Isidro9, Carlos Lopez-López10, Marcos Lopez-Hoyos11, Javier Llorca12,13, Jesús Agüero14, Benedicto Crespo-Facorro15,16, Ignacio Varela4, Miguel Ángel Piris17,**, Javier Crespo1,2,** and José Pedro Vaqué2,4,**

1Gastroenterology and Hepatology Unit, Hospital Universitario Marqués de Valdecilla, Santander, Spain

2Infection, Immunity and Digestive Pathology Group, IDIVAL, Santander, Spain

3Translational Hematopathology Group, IDIVAL, Instituto de Investigación Marqués de Valdecilla, Santander, Spain

4Departamento de Biología Molecular, Universidad de Cantabria (UC-IBBTEC), Santander, Spain

5Josep Carreras Leukemia Research Institute and School of Medicine, University of Barcelona, Barcelona, Spain

6Digestive Service, Hepatology Unit, Hospital Universitario Central de Asturias, Oviedo, Spain

7Universidad de Cantabria-IDIVAL, Santander, Spain

8General and Digestive Tract Surgery Service, Hospital Universitario Marqués de Valdecilla, Santander, Spain

9Biobanco-Hospital Universitario Central de Asturias, Oviedo, Spain

10Oncology Service, Hospital Universitario Marqués de Valdecilla, Santander, Spain

11Immunology Service, Hospital Universitario Marqués de Valdecilla, Santander, Spain

12Department of Epidemiology and Computational Biology, School of Medicine, University of Cantabria, Santander, Spain

13CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain

14Microbiology Service, University Hospital Marques de Valdecilla-IDIVAL, Santander, Spain

15Department of Psychiatry, Marqués de Valdecilla University Hospital-IDIVAL, Santander, Spain

16CIBERSAM, Centro de Investigación Biomédica en Red Salud Mental, Madrid, Spain

17Department of Pathology, Fundación Jiménez Díaz, Madrid, Spain

*These authors have contributed equally to this work

**Senior author

Correspondence to:

José Pedro Vaqué, email: [email protected]

Keywords: hepatocellular carcinoma; mutations; sorafenib; targeted therapy; AKT/mTOR

Received: January 16, 2018    Accepted: June 22, 2018    Published: July 20, 2018


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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