Lead


Lay summary
The relevance of aberrant function of the MET receptor tyrosine kinase to the pathogenesis of a broad spectrum of human malignancies has been firmly established over the last three decades and studies with first generation anti MET small molecule inhibitors strongly support the expectations of MET for becoming a central molecular target in cancer therapy, primarily of solid tumors.Apart of playing cardinal roles in the biology of cancer onset and maintenance, increasing data indicate that MET signaling may couple to the cellular DNA damage response machinery. This can eventually result in the shielding of tumor cells from cytotoxicity induced by therapeutical modalities, which largely act by inflicting DNA damage, such as ionizing radiation and radiomimetic drugs. In this respect, a recent work from our lab has shown that MET mutants are exclusively able to switch and activate a novel molecular axis that couples MET to DNA repair via homologous recombination.Hepatocellular carcinoma is a major malignant liver tumor in which deregulated MET expression has been documented. These tumors are commonly resistant to conventional chemotherapy, while radiation therapy is usually not applicable due to high toxicity towards normal liver tissue.Due to the emerging link between MET and DNA repair, the significance of the MET/hepatocyte growth factor axis to the pathogenesis of liver cancers whose incidence worldwide is constantly increasing and because the current therapeutic options for hepatocellular carcinoma patients are sobering, we focus mainly on the potential link between deregulated MET activity in liver models for these liver tumors and subsequent activation of DNA repair pathways. In addition, we study MET inhibition by small molecules as a means of increasing the sensitivity of these tumor cells towards DNA damaging agents. The major goal of this study is to provide an evidence for the relevance of the MET system to the activation of the DNA damage response in a tumor with high clinical significance and to develop experimental sensitization protocols with hopefully clinical applicative horizons.