Distinct Molecular Profiles and Drug Vulnerabilities in Pancreatic Metastases of Renal Cell Carcinoma

Abstract Pancreatic metastases (PM) of clear cell renal cell carcinoma (ccRCC) are rare, and little is known about them at patient level. The aim of this study was to define the patient-specific characteristics of PM-ccRCC and matching patient-derived cell (PDC) cultures. We describe the genomic and single-cell transcriptomic profiles of five patients with PM-ccRCC as well as the functional drug sensitivities of their PDCs­­. First, the patients’ tumors depicted both common and novel somatic mutations and copy number alterations, which were maintained in their PDCs. Second, we show that PM-ccRCC transcriptomes differ from previously reported signatures for bone metastasis and primary ccRCC. Finally, we find both shared (e.g., PIK3, mTOR inhibitors) and patient-specific (e.g., EGFR, MEK1/2 inhibitors) drug sensitivities. We use integrated multi-omics to illuminate pathway-level deregulations explaining drug sensitivities, and to propose patient-specific druggable pathways. Altogether, our findings suggest enriched molecular profiles in PM-ccRCC and target pathways for PM-ccRCC treatment.