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Extrinsic factors can mediate resistance to BRAF inhibition in central nervous system melanoma metastases
Author(s) -
Seifert Heike,
Hirata Eishu,
Gore Martin,
Khabra Komel,
Messiou Christina,
Larkin James,
Sahai Erik
Publication year - 2016
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/pcmr.12424
Subject(s) - vemurafenib , dabrafenib , melanoma , medicine , cancer research , central nervous system , cerebrospinal fluid , mapk/erk pathway , mek inhibitor , pathology , kinase , biology , metastatic melanoma , microbiology and biotechnology
Summary Here, we retrospectively review imaging of 68 consecutive unselected patients with BRAF V600‐mutant metastatic melanoma for organ‐specific response and progression on vemurafenib. Complete or partial responses were less often seen in the central nervous system ( CNS ) (36%) and bone (16%) compared to lung (89%), subcutaneous (83%), spleen (71%), liver (85%) and lymph nodes/soft tissue (83%), P < 0.001. CNS was also the most common site of progression. Based on this, we tested in vitro the efficacy of the BRAF inhibitors PLX 4720 and dabrafenib in the presence of cerebrospinal fluid ( CSF ). Exogenous CSF dramatically reduced cell death in response to both BRAF inhibitors. Effective cell killing was restored by co‐administration of a PI ‐3 kinase inhibitor. We conclude that the efficacy of vemurafenib is variable in different organs with CNS being particularly prone to resistance. Extrinsic factors, such as ERK ‐ and PI 3K‐activating factors in CSF , may mediate BRAF inhibitor resistance in the CNS .