Unknown

Dataset Information

0

BRAF(V600E) Kinase Domain Duplication Identified in Therapy-Refractory Melanoma Patient-Derived Xenografts.


ABSTRACT: The therapeutic landscape of melanoma is improving rapidly. Targeted inhibitors show promising results, but drug resistance often limits durable clinical responses. There is a need for in vivo systems that allow for mechanistic drug resistance studies and (combinatorial) treatment optimization. Therefore, we established a large collection of patient-derived xenografts (PDXs), derived from BRAF(V600E), NRAS(Q61), or BRAF(WT)/NRAS(WT) melanoma metastases prior to treatment with BRAF inhibitor and after resistance had occurred. Taking advantage of PDXs as a limitless source, we screened tumor lysates for resistance mechanisms. We identified a BRAF(V600E) protein harboring a kinase domain duplication (BRAF(V600E/DK)) in ?10% of the cases, both in PDXs and in an independent patient cohort. While BRAF(V600E/DK) depletion restored sensitivity to BRAF inhibition, a pan-RAF dimerization inhibitor effectively eliminated BRAF(V600E/DK)-expressing cells. These results illustrate the utility of this PDX platform and warrant clinical validation of BRAF dimerization inhibitors for this group of melanoma patients.

SUBMITTER: Kemper K 

PROVIDER: S-EPMC4929150 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

altmetric image

Publications


The therapeutic landscape of melanoma is improving rapidly. Targeted inhibitors show promising results, but drug resistance often limits durable clinical responses. There is a need for in vivo systems that allow for mechanistic drug resistance studies and (combinatorial) treatment optimization. Therefore, we established a large collection of patient-derived xenografts (PDXs), derived from BRAF(V600E), NRAS(Q61), or BRAF(WT)/NRAS(WT) melanoma metastases prior to treatment with BRAF inhibitor and  ...[more]

Similar Datasets

| S-EPMC3590666 | biostudies-other
| S-EPMC7141227 | biostudies-literature
| S-EPMC4001781 | biostudies-literature
| S-EPMC7216681 | biostudies-literature
| S-EPMC3758344 | biostudies-literature
| S-EPMC4844184 | biostudies-literature
| S-EPMC6195480 | biostudies-literature
| S-EPMC2848976 | biostudies-literature
| S-EPMC5669042 | biostudies-literature
| S-EPMC7418358 | biostudies-literature