期刊
PIGMENT CELL & MELANOMA RESEARCH
卷 29, 期 1, 页码 92-100出版社
WILEY
DOI: 10.1111/pcmr.12424
关键词
metastatic melanoma; central nervous system metastases; brain metastases; vemurafenib; resistance; BRAF mutant
资金
- Marie Curie FP7 grant [329047]
- Cancer Research UK
- NHS
- Cancer Research UK [15154] Funding Source: researchfish
- The Francis Crick Institute [10144, 10147] Funding Source: researchfish
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.
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