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

Susana Llerena,Nerea Martínez,Carlos Rodríguez De Lope,Javier Crespo,Agustín García-Blanco,Ignacio Varela,Ángela Puente,Pablo Isidro,Jesús Agüero,Helena Pisonero,Soraya Curiel-Olmo,María Teresa Arias-Loste,Javier Llorca,Miguel Santibáñez,Laura Cereceda,Antonio Agraz-Doblás ,Marcos López‐Hoyos ,L Martín-Ramos ,Miguel Á Piris ,Carlos López‐López ,Carmen Cagigas Fernandez ,Nuria García‐Díaz ,Marı́a Varela ,Benedicto Crespo‐Facorro ,Federico José Castillo Suescun ,Carmen Almaráz ,Jose P Vaqué

doi:10.18632/oncotarget.25766

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.

Highlights

Hepatocellular carcinoma (HCC hereafter) is the fifth most prevalent cancer and the third most frequent cause of cancer-related death worldwide, with up to 800K deaths in 2012 [1]
We hypothesized that case-specific mutational signatures within HCC cases could act as markers of important oncogenic mechanisms involved in HCC activities, including responses to sorafenib
Within our selection of genes, we included those already known to play a potential role in the disease (i.e., WNT, B-CATENIN and TP53) and others that have been implicated in specific signaling networks and that might serve as targets for therapy, e.g., JAK-STAT, PI3K-mTOR, MAPK and Receptors with Tyrosine Kinase Activity (RTKs)

Summary

Introduction

Hepatocellular carcinoma (HCC hereafter) is the fifth most prevalent cancer and the third most frequent cause of cancer-related death worldwide, with up to 800K deaths in 2012 [1]. It is a disease of increasing incidence and the leading cause of death among patients with cirrhosis. Outcomes are even worse for patients with intermediate or advanced stages (BCLC-B and C, respectively) [7] These patients will receive specific therapy that includes transarterial chemoembolization (for BCLC-B patients), which yields an increase in median survival from 16 to 24 months [8], or therapy with sorafenib (for BCLC-C patients). It is important to note that we currently lack molecular evidence to optimize the clinical benefits that HCC patients may gain from any of these therapies

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