Missing content? – Request curation!
Request curation for specific Genes, Variants, or PubMed publications.
Have questions, comments, or suggestions? - Let us know!
Email us at : ckbsupport@genomenon.com
| 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. | ||||||||||||
| 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 |
|---|---|---|---|---|---|
| ARID1B | Q127_Q131del | deletion | unknown | ARID1B Q127_Q131del results in the deletion of five amino acids in the Arid1b protein from amino acids 127 to 131 (UniProt.org). Q127_Q131del has been identified in the scientific literature (PMID: 36374558), but has not been biochemically characterized and therefore, its effect on Arid1b protein function is unknown (PubMed, Nov 2024). |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| ARID1B Q127_Q131del IDH1 R132L | cholangiocarcinoma | no benefit | Pamiparib | Preclinical - Pdx & cell culture | Actionable | In a preclinical study, a cholangiocarcinoma patient-derived xenograft (PDX) cell line harboring IDH1 R132L and ARID1B Q127_Q131del was 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 | 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 |
| ARID1B Q127_Q131del IDH1 R132L | cholangiocarcinoma | no benefit | Niraparib | Preclinical - Patient cell culture | Actionable | In a preclinical study, a cholangiocarcinoma patient-derived xenograft (PDX) cell line harboring IDH1 R132L and ARID1B Q127_Q131del was insensitive to Zejula (niraparib) 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 |
| ARID1B Q127_Q131del IDH1 R132L | cholangiocarcinoma | no benefit | Olaparib | Preclinical - Pdx & cell culture | Actionable | In a preclinical study, a cholangiocarcinoma patient-derived xenograft (PDX) cell line harboring IDH1 R132L and ARID1B Q127_Q131del was insensitive to Lynparza (olaparib) in culture and did not inhibit tumor growth in the patient-derived xenograft 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 |