Research Papers:
Applied diagnostics in liver cancer. Efficient combinations of sorafenib with targeted inhibitors blocking AKT/mTOR
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Abstract
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
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.
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PII: 25766