Inhibitor-induced counter-(up)regulation processes in gastric carcinoma: from secondary resistance mchanisms towards newly acquired tumor vulnerability

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Gastric cancer is one of the most frequent tumor entities and a leading cause of cancer-related deaths. In its often advanced and inoperable stage, conventional cytostatics show only limited efficacy. While in other tumor entities targeted inhibitors offer novel options in addition to classical chemotherapy, their use in gastric cancer has remained largely unsuccessful so far. For example, oncogenes like MET or HER receptors are often overexpressed, functionally relevant and a negative prognostic factor. Despite promising preclinical data, however, the use of specific inhibitors against these targets has remained disappointing in the clinics. 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. Indeed, own preliminary data demonstrated, upon treatment start with a specific inhibitor, the rapid upregulation of other HER receptors or ligands. 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. This also includes genetic characteristics and NGS diagnostics. Besides cell culture, studies will be conducted in various 2D- and 3D models in vitro and ex vivo (tissue slice-cultures) and will proceed towards the preclinical in vivo situation (tumor xenografts, patient-derived xenografts (PDX/AVATAR models)) and the ex vivo validation in patients’ tumors. Perspectively, therapy studies will also be performed in orthotopic xenograft-/ PDX models to be established here. Thus, the compensatory upregulation and (over-)activation of alternative oncogenic RTKs will not only be analyzed as possible reason for secondary resistance, to be avoided by combination therapies. Rather, it will be explicitly explored in sequential therapy regimens as novel promising avenue for enhancing therapeutic efficacies.