title: Intra- and inter-tumor heterogeneity in a vemurafenib-resistant melanoma patient and derived xenografts.
abstract: The development of targeted inhibitors, like vemurafenib, has greatly improved the clinical outcome of BRAF(V600E) metastatic melanoma. However, resistance to such compounds represents a formidable problem. Using whole-exome sequencing and functional analyses, we have investigated the nature and pleiotropy of vemurafenib resistance in a melanoma patient carrying multiple drug-resistant metastases. Resistance was caused by a plethora of mechanisms, all of which reactivated the MAPK pathway. In addition to three independent amplifications and an aberrant form of BRAF(V600E), we identified a new activating insertion in MEK1. This MEK1(T55delins) (RT) mutation could be traced back to a fraction of the pre-treatment lesion and not only provided protection against vemurafenib but also promoted local invasion of transplanted melanomas. Analysis of patient-derived xenografts (PDX) from therapy-refractory metastases revealed that multiple resistance mechanisms were present within one metastasis. This heterogeneity, both inter- and intra-tumorally, caused an incomplete capture in the PDX of the resistance mechanisms observed in the patient. In conclusion, vemurafenib resistance in a single patient can be established through distinct events, which may be preexisting. Furthermore, our results indicate that PDX may not harbor the full genetic heterogeneity seen in the patient's melanoma.
authors.affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Kristel
authors.initials: K
authors.lastname: Kemper
authors.affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Oscar
authors.initials: O
authors.lastname: Krijgsman
authors.affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Paulien
authors.initials: P
authors.lastname: Cornelissen-Steijger
authors.affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Aida
authors.initials: A
authors.lastname: Shahrabi
authors.affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Fleur
authors.initials: F
authors.lastname: Weeber
authors.affiliation: Division of Experimental Animal Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Ji-Ying
authors.initials: JY
authors.lastname: Song
authors.affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kuilman
authors.affiliation: Computational Cancer Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Vis
authors.affiliation: Computational Cancer Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Lodewyk F
authors.initials: LF
authors.lastname: Wessels
authors.affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Emile E
authors.initials: EE
authors.lastname: Voest
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Ton Nm
authors.initials: TN
authors.lastname: Schumacher
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Christian U
authors.initials: CU
authors.lastname: Blank
authors.affiliation: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: John B
authors.initials: JB
authors.lastname: Haanen
authors.affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands d.peeper@nki.nl.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Peeper
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D014644:Genetic Variation; D064593:Heterografts; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D008545:Melanoma / Q000188:drug therapy*; D009154:Mutation; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D017422:Sequence Analysis, DNA; D012878:Skin Neoplasms / Q000150:complications / Q000188:drug therapy*; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; D048493:Proto-Oncogene Proteins B-raf
keywords: Melanoma; drug resistance; patient‐derived xenografts; tumor heterogeneity