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Oncotarget. 2018 Jul 20;9(56):30869-30882. doi: 10.18632/oncotarget.25766. eCollection 2018 Jul 20.

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

Author information

1
Gastroenterology and Hepatology Unit, Hospital Universitario Marqués de Valdecilla, Santander, Spain.
2
Infection, Immunity and Digestive Pathology Group, IDIVAL, Santander, Spain.
3
Translational Hematopathology Group, IDIVAL, Instituto de Investigación Marqués de Valdecilla, Santander, Spain.
4
Departamento de Biología Molecular, Universidad de Cantabria (UC-IBBTEC), Santander, Spain.
5
Josep Carreras Leukemia Research Institute and School of Medicine, University of Barcelona, Barcelona, Spain.
6
Digestive Service, Hepatology Unit, Hospital Universitario Central de Asturias, Oviedo, Spain.
7
Universidad de Cantabria-IDIVAL, Santander, Spain.
8
General and Digestive Tract Surgery Service, Hospital Universitario Marqués de Valdecilla, Santander, Spain.
9
Biobanco-Hospital Universitario Central de Asturias, Oviedo, Spain.
10
Oncology Service, Hospital Universitario Marqués de Valdecilla, Santander, Spain.
11
Immunology Service, Hospital Universitario Marqués de Valdecilla, Santander, Spain.
12
Department of Epidemiology and Computational Biology, School of Medicine, University of Cantabria, Santander, Spain.
13
CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
14
Microbiology Service, University Hospital Marques de Valdecilla-IDIVAL, Santander, Spain.
15
Department of Psychiatry, Marqués de Valdecilla University Hospital-IDIVAL, Santander, Spain.
16
CIBERSAM, Centro de Investigación Biomédica en Red Salud Mental, Madrid, Spain.
17
Department of Pathology, Fundación Jiménez Díaz, Madrid, Spain.
#
Contributed equally

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.

KEYWORDS:

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

Conflict of interest statement

CONFLICTS OF INTEREST MV: Advisory boards, conferences, travel grants from Bayer. MAP has the following COI: Takeda-advisory board. Novartis, Amgen and Roche: Speaker bureau. CRL: Bayer HealthCare advisory board. JC: advisory board and conferences ABBVIE, MBS, GILEAD, JANSSEN, MSD and ROCHE. The other authors declare no conflicts of interest.

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