Maina Team publishes in Hepatology

Receptor tyrosine kinases (RTKs) ensure tissue homeostasis and their oncogenic activation leads to cancer. The Maina team at the IBDM has demonstrated the remarkable vulnerability of the liver to subtle changes in non-oncogenic RTK levels and has identified new potential therapies for liver cancer patient subgroups.

A Phosphokinome-based screen uncovers new drug synergies for cancer driven by liver-specific gain of non-oncogenic RTKs

Summary: Genetic mutations leading to oncogenic variants of receptor tyrosine kinases (RTKs) are frequent events during tumorigenesis. However, the cellular vulnerability to non-oncogenic RTK fluctuations has not been characterized. The Maina team has generated a unique mouse genetic system to explore in vivo vulnerability versus robustness to slight changes in non-oncogenic RTK levels. They demonstrated genetically that subtle increases in wild-type Met RTK levels in the liver are sufficient for spontaneous tumours to occur in mice (Alb-R26Met), thus illustrating how the shift from physiological to pathological conditions can result from slight perturbations in signalling dosage. In collaboration with the lab of Dr. J. Zucman-Rossi (Inserm), a panel of mouse tumour samples has been analysed, revealing that liver tumorigenesis modelled by Alb-R26Met mice corresponds to a subset of hepatocellular carcinoma (HCC) patients, thus establishing the clinical relevance of this HCC mouse model. The team has also elucidated the regulatory networks underlying tumorigenesis by combining a phosphokinome screen with bioinformatics analysis. The signalling changes observed when comparing Alb-R26Met HCC to control liver tissue were then used to design an “educated guess” drug screen, which led to the identification of new, deleterious synthetic lethal interactions. In particular, they reported synergistic effects of Mek, Rsk, and Cdk1/2 in combination with Bcl-XL inhibition on a panel of liver cancer cells. Focusing on Mek and Bcl-XL targeting, the team has mechanistically demonstrated concomitant downregulation of phospho-Erk and Mcl1 levels. Of note, a collaborative work with the lab of Pr. M. Roncalli (Univ. of Milan, Italy) revealed a pERK+/BCL-XL+/MCL1+ signature, deregulated in Alb-R26Met tumours, that characterizes a HCC subgroup of patients with poor prognosis.

These genetic studies highlight the heightened vulnerability of liver cells to subtle changes in non-oncogenic RTK levels, allowing them to acquire a molecular profile that facilitates the full tumorigenic program. Furthermore, outcomes uncover new synthetic lethal interactions as potential therapies for a cluster of HCC patients.

An "educated-guess" drug screen targeting signals found altered in the Alb-R26Met cancer model led to the identification of effective drug combinations against a subgroup of HCC corresponding to this mouse genetic system.

An “educated-guess” drug screen targeting signals found altered in the Alb-R26Met cancer model led to the identification of effective drug combinations against a subgroup of HCC corresponding to this mouse genetic system.

 

 

 

 

 

 

 

 

 

 

 

 

More information:

Yannan Fan1,#, Maria Arechederra1,#, Sylvie Richelme1, Fabrice Daian1, Chiara Novello2, Julien Calderaro3,4, Luca Di Tommaso2, Guillaume Morcrette5, Sandra Rebouissou5, Matteo Donadon6, Emanuela Morenghi7, Jessica Zucman-Rossi5, Massimo Roncalli2, Rosanna Dono1, and Flavio Maina1,*

1 Aix Marseille Univ, CNRS, Developmental Biology Institute of Marseille (IBDM), UMR 7288, Parc Scientifique de Luminy, Marseille, France.
2 Pathology Unit, Humanitas Clinical and Research Center, Rozzano, Milan, Italy and Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy.
3 APHP, Groupe Hospitalier Henri Mondor, Département de Pathologie, Créteil, France.
4 INSERM U955, Team 18, Institut Mondor de Recherche Biomédicale, Créteil, France.
5 Institut National de la Santé et de la Recherche Médicale (INSERM), UMR674, Génomique Fonctionnelle des Tumeurs Solides, Institut Universitaire d’Hematologie, Paris, France.
6 Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, Rozzano, Milan, Italy;
7 Biostatistics Unit, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
Hepatology 2017 Jun 6. doi: 10.1002/hep.29304.
* shared first authors

Contact: Flavio Maina – flavio.maina@univ-amu.fr