Abstract 2199: Establishment and high-throughput drug testing of multiple patient-derived cells from each renal cancer; intratumor heterogeneity of drug response and implications for precision medicine

Abstract

Abstract Renal cell cancer (RCC) has become a prototype example of the extensive intra-tumor genetic heterogeneity and clonal evolution of human cancers. There is, however, little information on how the genetic heterogeneity will impact on drug responsiveness of the cancer cells. Establishment of multiple patient-derived cells (PDCs) from individual patients may help us to understand genomic clonal evolution pathways in cancer, explore intratumor heterogeneity of drug response across tumors, as well as help to define combinatorial treatments needed to target multiple subclones in a cancer patient. Here, we established several PDCs from different tumor regions of four RCC patients, verified clonal relationships of the PDCs with each others and with the uncultured tumor tissue by genome sequencing. PDCs retained cancer-specific copy number alterations and mutations in driver genes such as VHL, PBRM1, PIK3C2A, KMD5C and TSC2 genes, but also showed differences indicating genetic heterogeneity and clonal evolution, and thus generating a set of natural isogenic variants. Comprehensive drug-sensitivity testing of the PDC clones with 460 oncology drugs was performed. The drug testing analysis identified shared vulnerability of the PDCs towards several approved RCC drugs, such as mTOR-inhibitor (temsirolimus) and multi-kinase-inhibitor (pazopanib). The individual RCC PDC clones from different tumor regions in one patient showed distinct drug response profiles, confirming that genomic heterogeneity contributes to the variability in drug responses. We developed a capability to map drug response evolution on top of genomic evolution in cancer. In conclusion, our study suggested that comparison of drug response profiles among multiple (isogenic) PDC variants from a cancer patient may be informative for i) assessing intratumor heterogeneity in drug response ii) elucidating pharmacogenomic biomarkers among natural isogenic cell variants and iii) identifying drugs and drug combinations that may kill the multiple cancer subclones in a patient. Funding: EU-FP7-Systems Microscopy Network of Excellence, Sigrid Juselius Foundation, Cancer Society of Finland, Academy of Finland, the Magnus Ehrnrooth Foundation, TEKES FiDiPro Fellow Grant and Knut and Alice Wallenberg Foundation. Citation Format: Khalid Saeed, Poojitha Ojamies, Teijo Pellinen, Samuli Eldfors, Riku Turkki, Johan Lundin, Harry Nisen, Petrus Järvinen, Kimmo Taari, Taija af Hällström, Antti Rannikko, Tuomas Mirtti, Olli Kallioniemi, Päivi Östling. Establishment and high-throughput drug testing of multiple patient-derived cells from each renal cancer; intratumor heterogeneity of drug response and implications for precision medicine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2199.