title: Co-clinical assessment identifies patterns of BRAF inhibitor resistance in melanoma.
abstract: Multiple mechanisms have been described that confer BRAF inhibitor resistance to melanomas, yet the basis of this resistance remains undefined in a sizable portion of patient samples. Here, we characterized samples from a set of patients with melanoma that included individuals at baseline diagnosis, on BRAF inhibitor treatment, and with resistant tumors at both the protein and RNA levels. Using RNA and DNA sequencing, we identified known resistance-conferring mutations in 50% (6 of 12) of the resistant samples. In parallel, targeted proteomic analysis by protein array categorized the resistant samples into 3 stable groups, 2 of which were characterized by reactivation of MAPK signaling to different levels and 1 that was MAPK independent. The molecular relevance of these classifications identified in patients was supported by both mutation data and the similarity of resistance patterns that emerged during a co-clinical trial in a genetically engineered mouse (GEM) model of melanoma that recapitulates the development of BRAF inhibitor resistance. Additionally, we defined candidate biomarkers in pre- and early-treatment patient samples that have potential for predicting clinical responses. On the basis of these observations, we suggest that BRAF inhibitor-resistant melanomas can be actionably classified using protein expression patterns, even without identification of the underlying genetic alteration.
authors.forename: Lawrence N
authors.initials: LN
authors.lastname: Kwong
authors.forename: Genevieve M
authors.initials: GM
authors.lastname: Boland
authors.forename: Dennie T
authors.initials: DT
authors.lastname: Frederick
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Helms
authors.forename: Ahmad T
authors.initials: AT
authors.lastname: Akid
authors.forename: John P
authors.initials: JP
authors.lastname: Miller
authors.forename: Shan
authors.initials: S
authors.lastname: Jiang
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Cooper
authors.forename: Xingzhi
authors.initials: X
authors.lastname: Song
authors.forename: Sahil
authors.initials: S
authors.lastname: Seth
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kamara
authors.forename: Alexei
authors.initials: A
authors.lastname: Protopopov
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wargo
authors.forename: Lynda
authors.initials: L
authors.lastname: Chin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004318:Doxycycline / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D010091:Oximes / Q000494:pharmacology / Q000627:therapeutic use; D051059:PTEN Phosphohydrolase / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D013629:Tamoxifen / Q000494:pharmacology; D019076:Transgenes
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D009363:Neoplasm Proteins; D010091:Oximes; D047428:Protein Kinase Inhibitors; D013629:Tamoxifen; C482119:BRAF protein, human; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D004318:Doxycycline; C561627:dabrafenib