Ex Vivo Drug Testing in Patient-derived Papillary Renal Cancer Cells Reveals EGFR and the BCL2 Family as Therapeutic Targets

Papillary Renal Cell Carcinoma (pRCC) is the second most frequent renal cancer subtype with different clinico-pathological signatures. Immune checkpoint inhibition alone or in combination with antiangiogenic inhibitors is considered the first-line treatment of advanced pRCC. Despite these new therapeutic solutions, the response rates of pRCC patients to these therapies are low. Rational drug development for metastatic pRCC patients based on the underlying molecular mechanism has become an urgent need. Our goal was to identify novel treatment options and to evaluate the extent to which genetic variants affect drug responses in advanced pRCCs. We established patient-derived cell cultures (PDCs) from pRCC patients. PDCs confirmed pRCC-specific copy number variations such as gains in chromosomes 7, 16 and 17. Whole Exome Sequencing revealed that PDCs retained mutations in pRCC-specific driver genes. Furthermore, we performed comprehensive drug sensitivity and resistance testing (DSRT) with 526 oncological drugs on six pRCC PDCs. Drug exposure to conventional treatments showed low efficacy in pRCC PDCs confirming the need for improved treatment strategies for this tumour entity. Remarkably, the DSRT results highlighted EGFR and Bcl-2 family inhibition as potential targets for the development of novel therapeutic solutions.