Functional and genomic characterization of patient-derived xenograft model to study the adaptation to mTORC1 inhibitor in clear cell renal cell carcinoma.

ABSTRACT: Resistance to the mechanistic target of rapamycin (mTOR) inhibitors, which are a standard treatment for advanced clear cell renal cell carcinoma (ccRCC), eventually develops in most cases. In this study, we established a patient-derived xenograft (PDX) model which acquired resistance to the mTOR inhibitor temsirolimus, and explored the underlying mechanisms of resistance acquisition. Temsirolimus was administered to PDX model mice, and one cohort of PDX models acquired resistance after repeated passages. PDX tumors were genetically analyzed by whole-exome sequencing and detected several genetic alterations specific to resistant tumors. Among them, mutations in ANKRD12 and DNMT1 were already identified in the early passage of a resistant PDX model, and we focused on a DNMT1 mutation as a po

SUBMITTER: Sakamoto H 

PROVIDER: S-EPMC7826464 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature