Extrinsic factors can mediate resistance to BRAF inhibition in central nervous system melanoma metastases

摘要: 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%) bone (16%) compared to lung (89%), subcutaneous (83%), spleen (71%), liver (85%) lymph nodes/soft tissue P < 0.001. CNS was also most common site progression. Based this, tested vitro efficacy inhibitors PLX4720 dabrafenib presence cerebrospinal fluid (CSF). Exogenous CSF dramatically reduced cell death both inhibitors. Effective killing restored by co-administration a PI-3 kinase inhibitor. We conclude that vemurafenib is variable different organs being particularly prone resistance. Extrinsic factors, such as ERK- PI3K-activating factors CSF, may mediate inhibitor resistance CNS.