Internal medicine

Biotechnology

Transcriptome

Exome sequencing

In vivo

PTEN

Hepatocellular carcinoma

Prostate cancer

Ponatinib

Biology

Gene

Cancer

Gene expression

Allele

Apoptosis

Imatinib

Metastasis

Microsatellite instability

Sorafenib

Myeloid leukemia

Sunitinib

Dasatinib

Organoid

Mutation

Cancer research

Genetics

Biochemistry

Microsatellite

Medicine

PI3K/AKT/mTOR pathway

Nature Communications

Therapy resistance and metastatic processes in prostate cancer (PCa) remain undefined, due to lack of experimental models that mimic different disease stages. We describe an androgen-dependent PCa patient-derived xenograft (PDX) model from treatment-naïve, soft tissue metastasis (PNPCa). RNA and whole-exome sequencing of the PDX tissue and organoids confirmed transcriptomic and genomic similarity to primary tumor. PNPCa harbors BRCA2 and CHD1 somatic mutations, shows an SPOP/FOXA1 -like transcriptomic signature and microsatellite instability, which occurs in 3% of advanced PCa and has never been modeled in vivo. Comparison of the treatment-naïve PNPCa with additional metastatic PDXs (BM18, LAPC9), in a medium-throughput organoid screen of FDA-approved compounds, revealed differential drug sensitivities. Multikinase inhibitors (ponatinib, sunitinib, sorafenib) were broadly effective on all PDX- and patient-derived organoids from advanced cases with acquired resistance to standard-of-care compounds. This proof-of-principle study may provide a preclinical tool to screen drug responses to standard-of-care and newly identified, repurposed compounds.

Patient-derived xenografts and organoids model therapy response in prostate cancer