Elimination of drug resistance

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Bonn researchers discover that a protein from fatty tissue precursors is the cause of treatment failure and develop a solution strategy

Urothelial carcinomas are malignant tumors that originate from the epithelium that lines the bladder and ureters, for example. They are still one of the most common types of cancer in Europe, especially in men. Prognostically relevant, in addition to early diagnosis, is above all the extent of the tumor, which ultimately determines the invasiveness of the treatment and the pharmacological therapy options.

Several studies have shown that genetic changes in the fibroblast growth factor receptor family, FGFR for short, play a central role in various types of cancer, including urothelial carcinoma. These receptors bind to various fibroblast growth factors FGF, which are signaling proteins that regulate cell growth, among other things. After binding, the activated FGFRs, which belong to the receptor tyrosine kinases, initiate a signaling cascade in the cell. The FGFR signaling pathway is thus involved in many central processes of cell development such as growth, differentiation, migration and cell survival. For this reason, a targeted cancer therapy consisting of the tyrosine kinase inhibitor erdafitinib, which blocks all subforms of the FGFR family or their downstream signaling pathways, has recently been used in addition to first-line therapy, i.e. the drug of first choice. "Unfortunately, subsequent clinical trials have shown rapid treatment failure with tumor progression and thus only a temporary survival benefit for the patients affected, which is due to the development of resistance mechanisms to erdafitinib," says Abdullah Alajati, Head of the Research Laboratory at the Department of Urology and Pediatric Urology at the University Hospital Bonn (UKB). He also conducts research at the University of Bonn.

HER3 antibody therapy breaks through resistance mechanism

When researching the underlying mechanisms, the team at the urology research laboratory led by Dr. Alajati therefore focused primarily on the influence of the tumor microenvironment, i.e. the direct environment of a tumor, which is made up of various components and has been little studied to date. "We found that a certain cell type, namely preadipocytes, i.e. precursor cells of the adipose tissue, are significantly involved in the development of resistance in tumor cells in urothelial carcinomas," says Alajati. These precursor adipocytes secrete a specific protein, neuregulin-1 (NRG1). As one of the most important ligands of the receptor tyrosine protein kinase ErbB-3, also known as HER3 (human epidermal growth factor receptor 3), NRG1 activates this alternative signaling pathway. However, this makes the tumor cells insensitive to the erdafitinib treatment. "We were able to show that switching off the NRG1 gene causes the cells to lose their resistance to erdatifinib, which makes it very clear that the NRG1 protein must be the mediator of this resistance," explains Alajati.

In order to confirm their hypothesis, the team used the antibody pertuzumab, which is already established in clinical practice and prevents activation of the NRG1/HER3 signaling pathway. "Interestingly, tumor growth is suppressed again with the simultaneous use of erdafitinib and pertuzumab, which was also confirmed in the mouse model by a positive influence on overall survival," says doctoral student Sana Hosni, research associate in the research laboratory of the Department of Urology and Pediatric Urology at the UKB. Viola Kilian, doctoral student at the University of Bonn, adds: ,,This means that the Erdafitinib resistance could be reversed by the additional blockade of HER3 signaling." The team hopes that these research results and the resulting hypotheses will be evaluated in further studies, especially clinical studies, in order to be able to use effective combination therapies in the treatment of patients with metastatic urothelial carcinoma in the near future. Since the NRG1/HER3 signaling pathway also plays an important role in other tumor entities such as breast cancer or ovarian cancer, our results could also be very relevant," says Alajati.