| First Author | Fan Y | Year | 2017 |
| Journal | Hepatology | Volume | 66 |
| Issue | 5 | Pages | 1644-1661 |
| PubMed ID | 28586114 | Mgi Jnum | J:364877 |
| Mgi Id | MGI:8173079 | Doi | 10.1002/hep.29304 |
| Citation | Fan Y, et al. (2017) A phosphokinome-based screen uncovers new drug synergies for cancer driven by liver-specific gain of nononcogenic receptor tyrosine kinases. Hepatology 66(5):1644-1661 |
| abstractText | Genetic mutations leading to oncogenic variants of receptor tyrosine kinases (RTKs) are frequent events during tumorigenesis; however, the cellular vulnerability to nononcogenic RTK fluctuations has not been characterized. Here, we demonstrated genetically that in the liver subtle increases in wild-type Met RTK levels are sufficient for spontaneous tumors in mice (Alb-R26(Met) ), 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 modeled by Alb-R26(Met) 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-R26(Met) 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 mitogen-activated protein kinase kinase, ribosomal S6 kinase, and cyclin-dependent kinase 1/2 in combination with Bcl-XL inhibition on a panel of liver cancer cells. Focusing on mitogen-activated protein kinase kinase and Bcl-XL targeting, we mechanistically demonstrated concomitant down-regulation of phosphorylated extracellular signal-regulated kinase and myeloid cell leukemia 1 levels. Of note, a phosphorylated extracellular signal-regulated kinase+/BCL-XL(+) /myeloid cell leukemia 1+ signature, deregulated in Alb-R26(Met) tumors, characterizes a subgroup of HCC patients with poor prognosis. CONCLUSION: Our genetic studies highlight the heightened vulnerability of liver cells to subtle changes in nononcogenic RTK levels, allowing them to acquire a molecular profile that facilitates the full tumorigenic program; furthermore, our outcomes uncover new synthetic lethal interactions as potential therapies for a cluster of HCC patients. (Hepatology 2017;66:1644-1661). |
