title: 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.
authors.affiliation: Vivarium and Transgenics Core, Van Andel Research Institute Grand Rapids, Michigan, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Monsma
authors.affiliation: Bioinformatics and Biostatistics Core, Van Andel Research Institute Grand Rapids, Michigan, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Cherba
authors.affiliation: Pathology and Biorepository Core, Van Andel Research Institute Grand Rapids, Michigan, USA.
authors.forename: Emily E
authors.initials: EE
authors.lastname: Eugster
authors.affiliation: Center for Translational Medicine, Van Andel Research Institute Grand Rapids, Michigan, USA.
authors.forename: Dawna L
authors.initials: DL
authors.lastname: Dylewski
authors.affiliation: Center for Translational Medicine, Van Andel Research Institute Grand Rapids, Michigan, USA.
authors.forename: Paula T
authors.initials: PT
authors.lastname: Davidson
authors.affiliation: College of Human Medicine, Michigan State University Grand Rapids, Michigan, USA.
authors.forename: Chelsea A
authors.initials: CA
authors.lastname: Peterson
authors.affiliation: Bioinformatics and Biostatistics Core, Van Andel Research Institute Grand Rapids, Michigan, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Borgman
authors.affiliation: Bioinformatics and Biostatistics Core, Van Andel Research Institute Grand Rapids, Michigan, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Winn
authors.affiliation: Bioinformatics and Biostatistics Core, Van Andel Research Institute Grand Rapids, Michigan, USA.
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Dykema
authors.affiliation: NuMedi Palo Alto, California, USA.
authors.forename: Craig P
authors.initials: CP
authors.lastname: Webb
authors.affiliation: Laboratory of Systems Biology, Van Andel Research Institute Grand Rapids, Michigan, USA.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: MacKeigan
authors.affiliation: Laboratory of Cancer and Developmental Cell Biology, Van Andel Research Institute Grand Rapids, Michigan, USA.
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Duesbery
authors.affiliation: Center for Translational Medicine, Van Andel Research Institute Grand Rapids, Michigan, USA ; College of Human Medicine, Michigan State University Grand Rapids, Michigan, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Nickoloff
authors.affiliation: Center for Translational Medicine, Van Andel Research Institute Grand Rapids, Michigan, USA ; Current address: Medimmune, One MedImmune Way Gaithersburg, MD, 20878, USA.
authors.forename: Noel R
authors.initials: NR
authors.lastname: Monks
keywords: BRAF; MEK; Melanoma; Vemurafenib; drug resistance; patient derived xenografts (PDX)