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

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 Mills, Keith T. Flaherty, Jennifer A. Wargo, Lynda Chin

Research output: Contribution to journalArticle

49 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1459-1470
Number of pages12
JournalJournal of Clinical Investigation
Volume125
Issue number4
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

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Melanoma
RNA Sequence Analysis
Protein Array Analysis
Mutation
DNA Sequence Analysis
Proteomics
Proteins
Biomarkers
Clinical Trials
RNA
Therapeutics
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Kwong, L. N., Boland, G. M., Frederick, D. T., Helms, T. L., Akid, A. T., Miller, J. P., ... Chin, L. (2015). Co-clinical assessment identifies patterns of BRAF inhibitor resistance in melanoma. Journal of Clinical Investigation, 125(4), 1459-1470. https://doi.org/10.1172/JCI78954

Co-clinical assessment identifies patterns of BRAF inhibitor resistance in melanoma. / Kwong, Lawrence N.; Boland, Genevieve M.; Frederick, Dennie T.; Helms, Timothy L.; Akid, Ahmad T.; Miller, John P.; Jiang, Shan; Cooper, Zachary A.; Song, Xingzhi; Seth, Sahil; Kamara, Jennifer; Protopopov, Alexei; Mills, Gordon; Flaherty, Keith T.; Wargo, Jennifer A.; Chin, Lynda.

In: Journal of Clinical Investigation, Vol. 125, No. 4, 01.01.2015, p. 1459-1470.

Research output: Contribution to journalArticle

Kwong, LN, Boland, GM, Frederick, DT, Helms, TL, Akid, AT, Miller, JP, Jiang, S, Cooper, ZA, Song, X, Seth, S, Kamara, J, Protopopov, A, Mills, G, Flaherty, KT, Wargo, JA & Chin, L 2015, 'Co-clinical assessment identifies patterns of BRAF inhibitor resistance in melanoma', Journal of Clinical Investigation, vol. 125, no. 4, pp. 1459-1470. https://doi.org/10.1172/JCI78954
Kwong LN, Boland GM, Frederick DT, Helms TL, Akid AT, Miller JP et al. Co-clinical assessment identifies patterns of BRAF inhibitor resistance in melanoma. Journal of Clinical Investigation. 2015 Jan 1;125(4):1459-1470. https://doi.org/10.1172/JCI78954
Kwong, Lawrence N. ; Boland, Genevieve M. ; Frederick, Dennie T. ; Helms, Timothy L. ; Akid, Ahmad T. ; Miller, John P. ; Jiang, Shan ; Cooper, Zachary A. ; Song, Xingzhi ; Seth, Sahil ; Kamara, Jennifer ; Protopopov, Alexei ; Mills, Gordon ; Flaherty, Keith T. ; Wargo, Jennifer A. ; Chin, Lynda. / Co-clinical assessment identifies patterns of BRAF inhibitor resistance in melanoma. In: Journal of Clinical Investigation. 2015 ; Vol. 125, No. 4. pp. 1459-1470.
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