Extrinsic factors can mediate resistance to BRAF inhibition in CNS melanoma metastases
journal contributionposted on 2020-10-01, 15:01 authored by Heike Seifert, Eishu Hirata, Martin Gore, Komel Khabra, Christina Messiou, James Larkin, Erik Sahai
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.
BRAF mutantbrain metastasescentral nervous system metastasesmetastatic melanomaresistancevemurafenibAdolescentAdultAgedCell DeathCell SurvivalCentral Nervous System NeoplasmsDisease ProgressionDrug Resistance, NeoplasmFemaleHumansIndolesMaleMelanomaMiddle AgedOrgan SpecificityPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsProtein Kinase InhibitorsProto-Oncogene Proteins B-rafSulfonamidesYoung AdultSahai FC001144Dermatology & Venereal Diseases06 Biological Sciences11 Medical and Health Sciences