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Ref Type Journal Article
PMID (36374558)
Authors Serra-Camprubí Q, Verdaguer H, Oliveros W, Lupión-Garcia N, Llop-Guevara A, Molina C, Vila-Casadesús M, Turpin A, Neuzillet C, Frigola J, Querol J, Yáñez-Bartolomé M, Castet F, Fabregat-Franco C, Escudero-Iriarte C, Escorihuela M, Arenas EJ, Bernadó-Morales C, Haro N, Giles FJ, Pozo ÓJ, Miquel JM, Nuciforo PG, Vivancos A, Melé M, Serra V, Arribas J, Tabernero J, Peiró S, Macarulla T, Tian TV
Title Human Metastatic Cholangiocarcinoma Patient-Derived Xenografts and Tumoroids for Preclinical Drug Evaluation.
URL
Abstract Text Cholangiocarcinoma (CCA) is usually diagnosed at advanced stages, with limited therapeutic options. Preclinical models focused on unresectable metastatic CCA are necessary to develop rational treatments. Pathogenic mutations in IDH1/2, ARID1A/B, BAP1, and BRCA1/2 have been identified in 30%-50% of patients with CCA. Several types of tumor cells harboring these mutations exhibit homologous recombination deficiency (HRD) phenotype with enhanced sensitivity to PARP inhibitors (PARPi). However, PARPi treatment has not yet been tested for effectiveness in patient-derived models of advanced CCA.We have established a collection of patient-derived xenografts from patients with unresectable metastatic CCA (CCA_PDX). The CCA_PDXs were characterized at both histopathologic and genomic levels. We optimized a protocol to generate CCA tumoroids from CCA_PDXs. We tested the effects of PARPis in both CCA tumoroids and CCA_PDXs. Finally, we used the RAD51 assay to evaluate the HRD status of CCA tissues.This collection of CCA_PDXs recapitulates the histopathologic and molecular features of their original tumors. PARPi treatments inhibited the growth of CCA tumoroids and CCA_PDXs with pathogenic mutations of BRCA2, but not those with mutations of IDH1, ARID1A, or BAP1. In line with these findings, only CCA_PDX and CCA patient biopsy samples with mutations of BRCA2 showed RAD51 scores compatible with HRD.Our results suggest that patients with advanced CCA with pathogenic mutations of BRCA2, but not those with mutations of IDH1, ARID1A, or BAP1, are likely to benefit from PARPi therapy. This collection of CCA_PDXs provides new opportunities for evaluating drug response and prioritizing clinical trials.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ARID1A A35Gfs*76 cholangiocarcinoma no benefit Niraparib Preclinical - Patient cell culture Actionable In a preclinical study, a cholangiocarcinoma patient-derived xenograft (PDX) cell line harboring ARID1A A35Gfs*76 was insensitive to Zejula (niraparib) in culture (PMID: 36374558). 36374558
ARID1A A35Gfs*76 cholangiocarcinoma no benefit Pamiparib Preclinical - Patient cell culture Actionable In a preclinical study, a cholangiocarcinoma patient-derived xenograft (PDX) cell line harboring ARID1A A35Gfs*76 was insensitive to Pamiparib (BGB-290) in culture (PMID: 36374558). 36374558
IDH1 R132C cholangiocarcinoma no benefit Pamiparib Preclinical - Pdx & cell culture Actionable In a preclinical study, cholangiocarcinoma patient-derived xenograft (PDX) cell lines harboring IDH1 R132C were insensitive to Pamiparib (BGB-290) in culture and did not inhibit tumor growth in the patient-derived xenograft (PDX) model (PMID: 36374558). 36374558
IDH1 R132C cholangiocarcinoma no benefit Olaparib Preclinical - Pdx & cell culture Actionable In a preclinical study, cholangiocarcinoma patient-derived xenograft (PDX) cell lines harboring IDH1 R132C were insensitive to Lynparza (olaparib) in culture and did not inhibit tumor growth in the patient-derived xenograft (PDX) model (PMID: 36374558). 36374558
IDH1 R132C cholangiocarcinoma no benefit Niraparib Preclinical - Patient cell culture Actionable In a preclinical study, cholangiocarcinoma patient-derived xenograft (PDX) cell lines harboring IDH1 R132C were insensitive to Zejula (niraparib) in culture (PMID: 36374558). 36374558
ARID1A A35Gfs*76 cholangiocarcinoma no benefit Olaparib Preclinical - Patient cell culture Actionable In a preclinical study, a cholangiocarcinoma patient-derived xenograft (PDX) cell line harboring ARID1A A35Gfs*76 was insensitive to Lynparza (olaparib) in culture (PMID: 36374558). 36374558