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

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.

Tumor Microenvironment and Differential Responses to Therapy

“…Tumor necrosis factor a (TNF-a) production by tumor-associated macrophages can also protect melanoma cells from BRAF therapies (Smith et al 2014) and soluble factors in cerebrospinal fluid can reduce the efficacy of BRAF inhibitors. This may partially explain the poor response of brain metastases to vemurafenib (Seifert et al 2016). Fibroblast-derived HGF has also been implicated in the resistance of EGFR mutant lung cancer to EGFR inhibitors (Wang et al 2009).…”

Overcoming resistance to BRAF inhibitors

“…GRO activates CXCR2 signaling in melanoma cells, which overcomes BRAF inhibition as well as BRAF/MEK combination therapies (73). BRAF inhibition shows also efficacy in brain metastases (74), but it has been suggested that ERK-and PI3K-activating extrinsic factors contained in cerebrospinal fluid might contribute to BRAF inhibitor resistance in this setting (75). Finally, upon BRAF inhibitor treatment, specific soluble factors can sustain the proliferation of innate resistant cells that normally present as slow cycling cells in therapy naïve tumors (76,77).…”

Melanoma Brain Metastases

“…This pathway has also been associated with resistance to BRAF inhibitors, and preclinical in vitro and in vivo studies support that PI3K pathway inhibitors may be an effective strategy for MBMs as single agents or in combination with BRAF inhibitors. 15,17,18 A phase II trial of the pan-PI3K inhibitor buperlisib (BKM120) in patients with MBMs is currently ongoing [Table 2]. Additional studies support that increased signaling by the JAK-STAT signaling pathway may be associated with MBM, and a phase II trial of the STAT3 inhibitor WP-1066 in MBM patients is underway.…”