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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.

SUBMITTER: Seifert H

PROVIDER: S-EPMC4737278 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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

Seifert Heike H Hirata Eishu E Gore Martin M Khabra Komel K Messiou Christina C Larkin James J Sahai Erik E

Pigment cell & melanoma research 20151103 1

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 ...[more]

PMID: 26414886

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Project description:Combined MEK-BRAF inhibition is a well-established treatment strategy in BRAF-mutated cancer, most prominently in malignant melanoma with durable responses being achieved through this targeted therapy. However, a subset of patients face primary unresponsiveness despite presence of the activating mutation at position V600E, and others acquire resistance under treatment. Underlying resistance mechanisms are largely unknown, and diagnostic tests to predict tumor response to BRAF-MEK inhibitor treatment are unavailable. Multiple myeloma represents the second most common hematologic malignancy, and point mutations in BRAF are detectable in about 10% of patients. Targeted inhibition has been successfully applied, with mixed responses observed in a substantial subset of patients mirroring the widespread spatial heterogeneity in this genomically complex disease. Central nervous system (CNS) involvement is an extremely rare, extramedullary form of multiple myeloma that can be diagnosed in less than 1% of patients. It is considered an ultimate high-risk feature, associated with unfavorable cytogenetics, and, even with intense treatment applied, survival is short, reaching less than 12 months in most cases. Here we not only describe the first patient with an extramedullary CNS relapse responding to targeted dabrafenib and trametinib treatment, we furthermore provide evidence that a point mutation within the capicua transcriptional repressor (CIC) gene mediated the acquired resistance in this patient. KEY POINTS: BRAF mutations constitute an attractive druggable target in multiple myeloma. This is the first genomic dissection of the central nervous system involvement in a multiple myeloma patient harboring a druggable BRAFV600E mutation. Deep genomic characterization of the extramedullary lesion prompted a personalized therapeutic approach. Acquisition of CIC mutation confers a mechanism of BRAF-MEK inhibitor drug resistance in multiple myeloma. The in silico interrogation of the CoMMpass clinical study revealed 10 patients with somatic mutations of CIC and its downregulation at gene expression level in multiple myeloma. CIC gene silencing decreases the sensitivity of multiple myeloma cells to BRAF-MEK inhibition in vitro. The correlation between CIC downregulation and ETV4/5 nuclear factor expression in multiple myeloma BRAF-mutant cells is shown for the first time. CIC mutation, its downregulation, and the related downstream effect on MMP24 support disseminative potential providing new clues in the extramedullary biology definition.

Project description:BackgroundPatients with melanoma and central nervous system (CNS) metastases have poor survival outcomes. We investigated real-world treatment patterns and overall survival (OS) of patients with melanoma and CNS metastases.MethodsA retrospective analysis utilizing a nationwide de-identified electronic health record-derived database was undertaken in patients diagnosed with advanced melanoma between January 2011 and September 2018. Patients with any visit ≤90 days of metastatic diagnosis and with confirmed CNS metastases were included.ResultsOf 3473 patients diagnosed with advanced melanoma, 791 patients with confirmed CNS metastases were identified and included in this analysis. Synchronous CNS metastasis (≤30 days of metastatic diagnosis) was associated with longer median OS than metachronous CNS metastasis (>30 days after metastatic diagnosis, 0.58 vs 0.42 years). Stereotactic radiosurgery (SRS) was the most common treatment (40.5%) alone or in combination with other local or systemic therapies, being more frequent in patients diagnosed in 2015+ versus 2011-2014 (44.1% vs 35.5%, respectively). The most common systemic treatment was immune checkpoint inhibitors (ICIs; 30.5%), predominantly anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) alone (2011-2014) and anti-programmed death-1 alone or in combination with anti-CTLA-4 (2015+). Median OS was longest in SRS-treated patients (1.17 years) regardless of number of CNS metastases. Median OS for SRS-treated patients increased from 0.83 years (2011-2014) to 1.75 years (2015+). In multivariable analysis, the effect of SRS remained significant after adjustment for sex, race, intracranial and extracranial disease burden, and timing of CNS metastases. Interaction testing to examine potential synergy between SRS/whole-brain radiation therapy and ICIs found no significant interaction.ConclusionsDespite advances in treatment, patients with melanoma and CNS metastases have poor survival outcomes. Prevalence of SRS increased over time and was associated with improved outcomes.

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

Publications

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

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