Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews...
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • Allergy (Apr 2019)
    • Biology of familial cancer predisposition syndromes (Feb 2019)
    • Mitochondrial dysfunction in disease (Aug 2018)
    • Lipid mediators of disease (Jul 2018)
    • Cellular senescence in human disease (Apr 2018)
    • View all review series...
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Scientific Show Stoppers
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • About
  • Editors
  • Consulting Editors
  • For authors
  • Current issue
  • Past issues
  • By specialty
  • Subscribe
  • Alerts
  • Advertise
  • Contact
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • Brief Reports
  • Technical Advances
  • Commentaries
  • Editorials
  • Hindsight
  • Review series
  • Reviews
  • The Attending Physician
  • First Author Perspectives
  • Scientific Show Stoppers
  • Top read articles
  • Concise Communication
Co-clinical assessment identifies patterns of BRAF inhibitor resistance in melanoma
Lawrence N. Kwong, … , Jennifer A. Wargo, Lynda Chin
Lawrence N. Kwong, … , Jennifer A. Wargo, Lynda Chin
Published April 1, 2015; First published February 23, 2015
Citation Information: J Clin Invest. 2015;125(4):1459-1470. https://doi.org/10.1172/JCI78954.
View: Text | PDF
Categories: Research Article Oncology

Co-clinical assessment identifies patterns of BRAF inhibitor resistance in melanoma

  • Text
  • PDF
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

Lawrence N. Kwong, Genevieve M. Boland, Dennie T. Frederick, Timothy L. Helms, Ahmad T. Akid, John P. Miller, Shan Jiang, Zachary A. Cooper, Xingzhi Song, Sahil Seth, Jennifer Kamara, Alexei Protopopov, Gordon B. Mills, Keith T. Flaherty, Jennifer A. Wargo, Lynda Chin

×

Figure 5

Several RTKs confer resistance to BRAF inhibition.

Options: View larger image (or click on image) Download as PowerPoint
Several RTKs confer resistance to BRAF inhibition.
(A) Effects of candid...
(A) Effects of candidate gene overexpression on dabrafenib sensitivity in the BRAFV600E melanoma cell line A375. Results represent crystal violet measurements normalized to the GFP control. (B) RPPA analysis of candidate gene overexpression. The rightmost columns represent treated lines normalized to treated GFP. All lines were assayed in technical duplicates. (C) Xenografts from the A375 pHAGE lines, untreated or treated with PLX4720 chow. (D) Staining of A375 pHAGE tumors: red, p-ERK; blue, DAPI.
Follow JCI:
Copyright © 2019 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts