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RP 9

Verena Taudte / Niklas Gremke: Thymidine phosphorylase secretion: a druggable metabolic alteration in the microenvironment of PI3K-inhibitor-resistant breast cancer

AIM: A plethora of different molecular targeted therapies (e.g. PI3 Kinase inhibitors, PI3Ki) have entered clinical practice and improved the therapy of hormone receptor-positive, HER2neu-negative, and PIK3CA-mutated metastasized breast cancer (BC). However, the phenotypic plasticity allows tumors to rapidly evolve drug-resistant subclones. Based on our previous data we will investigate how the secreted enzyme thymidine phosphorylase (TYMP) and upregulated thymidine metabolites reprogram the extracellular space and alter the metabolism of stromal and immune cells with potential functional consequences on intercellular communication networks of stromal and immune cells.

STATE of the ART: Targeted agents have revolutionized cancer therapy and led to significant breakthroughs based on their superior clinical benefits compared to prior standard-of-care regimens. The PI3K signaling pathway is a promising target in PIK3CA-mutated BC and inhibitors are available, however, many patients develop resistance to therapy ultimately leading to therapy failure. This resistance emerges as a result of cancer cells evolving and co-opting endogenous stress mitigation pathways that allow them to deal with therapy-induced stress. Moreover, these compensatory metabolic routes not only affect the cancer cells themselves but also other cells present in the tumor microenvironment (TME), such as immune or stromal cells. Therefore, the elucidation of the molecular mechanisms of therapeutic resistance and its effect on the TME is urgently needed to develop strategies in order to circumvent this drawback.