Inhibitor-induzierte Gegenregulationsprozesse im Magenkarzinom: von sekundären Resistenzmechanismen zu neu akquirierter Tumor-Vulnerabilität

Gastric cancer is one of the most frequent tumor entities and a leading cause of cancer-related deaths. While in other tumor entities targeted inhibitors offer novel options in addition to classical chemotherapy, their clinical use in gastric cancer has remained largely unsuccessful so far. Despite promising preclinical data, the use of specific inhibitors against these targets has remained disappointing in the clinical setting. Thus, the improvement of personalized therapies requires the identification of factors responsible for primary or secondary resistance. In this context, the compensatory upregulation of other oncogenic (non-target) receptor tyrosine kinases (RTKs) may well be of major importance. Interestingly, this compensatory upregulation with concomitant (over-)activation of alternative oncogenic RTKs may not only be a major reason for secondary resistance. Rather, it could also offer novel therapeutic options.

On this basis, this project aims at (i) the in-depth characterization of inhibitor- or RNAi/knockdown-induced alterations in the expression of oncogenic RTKs, the identification of other candidates by proteomics and the analysis of cellular and molecular effects of these counter-(up-)regulation processes, (ii) the definition of promising combinations of specific inhibitors / knockdowns, for testing with regard to additive/synergistic effects, (iii) the exploration of sequential therapy regimes, based on the concept of secondary resistance induction as "acquired vulnerability". This „second hit concept" with established inhibitors may also include dose reductions compared to single treatment, (iv) the validation of most promising combinations and sequential therapy regimes on primary tumors, using ex vivo tissue slice culture models from fresh patient tumors.​​