title: Extrinsic factors can mediate resistance to BRAF inhibition in central nervous system melanoma metastases.
abstract: 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.
authors.affiliation: Department of Medical Oncology, Royal Marsden NHS Trust, London, UK.
authors.forename: Heike
authors.identifier: http://orcid.org/0000-0003-3052-1651
authors.initials: H
authors.lastname: Seifert
authors.affiliation: Tumour Cell Biology Laboratory, The Francis Crick Institute, London, UK.|Department of Oncologic Pathology, Kanazawa Medical University, Kahoku-gun, Ishikawa, Japan.
authors.forename: Eishu
authors.initials: E
authors.lastname: Hirata
authors.affiliation: Department of Medical Oncology, Royal Marsden NHS Trust, London, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Gore
authors.affiliation: Department of Medical Oncology, Royal Marsden NHS Trust, London, UK.
authors.forename: Komel
authors.initials: K
authors.lastname: Khabra
authors.affiliation: Department of Medical Oncology, Royal Marsden NHS Trust, London, UK.
authors.forename: Christina
authors.initials: C
authors.lastname: Messiou
authors.affiliation: Department of Medical Oncology, Royal Marsden NHS Trust, London, UK.
authors.forename: James
authors.initials: J
authors.lastname: Larkin
authors.affiliation: Tumour Cell Biology Laboratory, The Francis Crick Institute, London, UK.
authors.forename: Erik
authors.initials: E
authors.lastname: Sahai
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016543:Central Nervous System Neoplasms / Q000134:cerebrospinal fluid / Q000201:enzymology / Q000556:secondary*; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008545:Melanoma / Q000134:cerebrospinal fluid / Q000473:pathology*; D008875:Middle Aged; D009928:Organ Specificity / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D055815:Young Adult
chemical_list: D007211:Indoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D013449:Sulfonamides; C528407:PLX 4720
keywords: BRAF mutant; brain metastases; central nervous system metastases; metastatic melanoma; resistance; vemurafenib