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. Here, we demonstrated genetically that liver subtle increases in wild-type Met RTK levels are sufficient for spontaneous tumors in mice (Alb-R26Met ), conceptually illustrating how the shift from physiological to pathological conditions results from slight perturbations in signaling dosage. By analyzing 96 different genes in a panel of tumor samples, we demonstrated 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. We elucidated the regulatory networks underlying tumorigenesis by combining a phosphokinome screen with bioinformatics analysis. We then used the signaling diversity results obtained from Alb-R26Met HCC versus control livers to design an "educated guess" drug screen, which led to the identification of new, deleterious synthetic lethal interactions. In particular, we report 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, we mechanistically demonstrated concomitant downregulation of phospho-Erk and Mcl1 levels. Of note, a pERK+ /BCL-XL+ /MCL1+ signature, deregulated in Alb-R26Met tumors, characterizes a HCC subgroup of patients with poor prognosis. CONCLUSION: Our 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, our outcomes highlight new synthetic lethal interactions as potential therapies for a cluster of HCC patients. This article is protected by copyright. All rights reserved.
A Phosphokinome-based screen uncovers new drug synergies for cancer driven by liver-specific gain of non-oncogenic RTKs
Di Tommaso L;Donadon M;
2017-01-01
Abstract
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. Here, we demonstrated genetically that liver subtle increases in wild-type Met RTK levels are sufficient for spontaneous tumors in mice (Alb-R26Met ), conceptually illustrating how the shift from physiological to pathological conditions results from slight perturbations in signaling dosage. By analyzing 96 different genes in a panel of tumor samples, we demonstrated 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. We elucidated the regulatory networks underlying tumorigenesis by combining a phosphokinome screen with bioinformatics analysis. We then used the signaling diversity results obtained from Alb-R26Met HCC versus control livers to design an "educated guess" drug screen, which led to the identification of new, deleterious synthetic lethal interactions. In particular, we report 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, we mechanistically demonstrated concomitant downregulation of phospho-Erk and Mcl1 levels. Of note, a pERK+ /BCL-XL+ /MCL1+ signature, deregulated in Alb-R26Met tumors, characterizes a HCC subgroup of patients with poor prognosis. CONCLUSION: Our 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, our outcomes highlight new synthetic lethal interactions as potential therapies for a cluster of HCC patients. This article is protected by copyright. All rights reserved.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
