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

Heike Seifert,Christina Messiou,Komel Khabra,Erik Sahai,James Larkin,Eishu Hirata,Martin Gore

doi:10.1111/pcmr.12424

Heike Seifert, Christina Messiou + Show 5 more

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https://doi.org/10.1111/pcmr.12424

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Abstract

SummaryHere, 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.

Highlights

The selective BRAF inhibitors vemurafenib and dabrafenib are systemic treatments in patients with metastatic melanoma harbouring a V600 BRAF mutation, which accounts for roughly half cutaneous melanoma
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 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)

Summary

Introduction

The selective BRAF inhibitors vemurafenib and dabrafenib are systemic treatments in patients with metastatic melanoma harbouring a V600 BRAF mutation, which accounts for roughly half cutaneous melanoma. BRAF V600 mutations activate the ERK/MAPK pathway, which plays an essential role in cell proliferation, differentiation and survival. Treatment with BRAF inhibitors results in high objective response rates, but progression occurs after an average of 6–7 months (McArthur et al, 2014). Extensively studied over the last few years, resistance mechanisms to BRAF-targeted kinase inhibitors have not yet been fully understood (Bucheit and Davies, 2014). Multiple primary and acquired resistance mechanisms have been identified including those that lead to reactivation of the MAPK pathway and MAPKindependent pathways, such as the PI3K/AKT/mTOR/ cyclin D1/CDK4 retinoblastoma pathways (Bucheit and Davies, 2014). If progression occurs in one organ with ongoing response, in other organs, melanoma cell extrinsic factors may play a crucial role

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