Effects of BRAF inhibitors on human melanoma tissue before treatment, early during treatment, and on progression

Georgina V. Long*, James S. Wilmott, Lauren E. Haydu, Varsha Tembe, Raghwa Sharma, Helen Rizos, John F. Thompson, Julie Howle, Richard A. Scolyer, Richard F. Kefford

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)

Abstract

Selective BRAF inhibitors (BRAFi) are a standard of care for the treatment of BRAFV600-mutant metastatic melanoma. We analyzed a unique set of serial triplicate human metastatic melanoma tumor biopsies to identify biomarkers of BRAFi response and resistance. Morphologic features and immunohistochemical biomarkers were analyzed in 37 metastatic melanoma biopsies at pretreatment (PRE), early during treatment (EDT), and on progression (PROG) from 15 patients treated with a BRAFi and correlated with response and outcome. At EDT, proliferative markers decreased regardless of response, whereas markers of cell death increased in responders. High expression of nuclear p27 at baseline was the strongest predictor of a poorer OS and predicted worse response. The results show that BRAFi are universally antiproliferative, regardless of clinical response, whereas markers of cell death increased only in responders. The addition of therapies targeting the cell cycle machinery may improve the response and duration of BRAFi, and investigation of the mechanisms of apoptosis may provide additional therapeutic targets.

Original languageEnglish
Pages (from-to)499-508
Number of pages10
JournalPigment Cell and Melanoma Research
Volume26
Issue number4
DOIs
Publication statusPublished - Jul 2013
Externally publishedYes

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