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

Eur Urol Focus. 2023 Mar 16:S2405-4569(23)00067-6. doi: 10.1016/j.euf.2023.03.005. Online ahead of print.


BACKGROUND: Immune checkpoint inhibitors and antiangiogenic agents are used for first-line treatment of advanced papillary renal cell carcinoma (pRCC) but pRCC response rates to these therapies are low.

OBJECTIVE: To generate and characterise a functional ex vivo model to identify novel treatment options in advanced pRCC.

DESIGN, SETTING, AND PARTICIPANTS: We established patient-derived cell cultures (PDCs) from seven pRCC samples from patients and characterised them via genomic analysis and drug profiling.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Comprehensive molecular characterisation in terms of copy number analysis and whole-exome sequencing confirmed the concordance of pRCC PDCs with the original tumours. We evaluated their sensitivity to novel drugs by generating drug scores for each PDC.

RESULTS AND LIMITATIONS: 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. We performed drug screening with 526 novel and oncological compounds. Whereas exposure to conventional drugs showed low efficacy, the results highlighted EGFR and BCL2 family inhibition as the most effective targets in our pRCC PDCs.

CONCLUSIONS: High-throughput drug testing on newly established pRCC PDCs revealed that inhibition of EGFR and BCL2 family members could be a therapeutic strategy in pRCC.

PATIENT SUMMARY: We used a new approach to generate patient-derived cells from a specific type of kidney cancer. We showed that these cells have the same genetic background as the original tumour and can be used as models to study novel treatment options for this type of kidney cancer.

PMID:36933996 | DOI:10.1016/j.euf.2023.03.005

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