Unknown

Dataset Information

0

Melanoma patient derived xenografts acquire distinct Vemurafenib resistance mechanisms.


ABSTRACT: Variable clinical responses, tumor heterogeneity, and drug resistance reduce long-term survival outcomes for metastatic melanoma patients. To guide and accelerate drug development, we characterized tumor responses for five melanoma patient derived xenograft models treated with Vemurafenib. Three BRAF(V600E) models showed acquired drug resistance, one BRAF(V600E) model had a complete and durable response, and a BRAF(V600V) model was expectedly unresponsive. In progressing tumors, a variety of resistance mechanisms to BRAF inhibition were uncovered, including mutant BRAF alternative splicing, NRAS mutation, COT (MAP3K8) overexpression, and increased mutant BRAF gene amplification and copy number. The resistance mechanisms among the patient derived xenograft models were similar to the resistance pathways identified in clinical specimens from patients progressing on BRAF inhibitor therapy. In addition, there was both inter- and intra-patient heterogeneity in resistance mechanisms, accompanied by heterogeneous pERK expression immunostaining profiles. MEK monotherapy of Vemurafenib-resistant tumors caused toxicity and acquired drug resistance. However, tumors were eradicated when Vemurafenib was combined the MEK inhibitor. The diversity of drug responses among the xenograft models; the distinct mechanisms of resistance; and the ability to overcome resistance by the addition of a MEK inhibitor provide a scheduling rationale for clinical trials of next-generation drug combinations.

SUBMITTER: Monsma DJ 

PROVIDER: S-EPMC4473327 | BioStudies | 2015-01-01

REPOSITORIES: biostudies

Similar Datasets

2013-01-01 | S-EPMC3930354 | BioStudies
2020-01-01 | S-EPMC7449901 | BioStudies
2016-01-01 | S-EPMC4893919 | BioStudies
2015-01-01 | S-EPMC4435825 | BioStudies
2014-01-01 | S-EPMC3988223 | BioStudies
2015-01-01 | S-EPMC4627280 | BioStudies
2013-01-01 | S-EPMC3758344 | BioStudies
2013-01-01 | S-EPMC4086218 | BioStudies
2018-01-01 | S-EPMC6261462 | BioStudies
2019-01-01 | S-EPMC6822426 | BioStudies