Extrinsic factors can mediate resistance to BRAF inhibition in CNS melanoma metastases
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Heike Seifert Eishu Hirata Martin Gore Komel Khabra Christina Messiou James Larkin Erik SahaiAbstract
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 PLX4720 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 PI3K-activating factors in CSF, may mediate BRAF inhibitor resistance in the CNS.
Journal details
Journal Pigment Cell & Melanoma Research
Volume 29
Issue number 1
Pages 92-100
Available online
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Publisher website (DOI) 10.1111/pcmr.12424
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Europe PubMed Central 26414886
Pubmed 26414886
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