An adaptive signaling network in melanoma inflammatory niches confers tolerance to MAPK signaling inhibition

Young, Helen; Rowling, Emily J.; Bugatti, Mattia; Giurisato, Emanuele; Luheshi, Nadia; Arozarena, Imanol; Acosta, Juan Carlos; Kamarashev, Jivko; Frederick, Dennie T.; Cooper, Zachary A.; Reuben, Alexandre; Gil, Jesús; Flaherty, Keith T.; Wargo, Jennifer A.; Vermi, William; Smith, Michael P.; Wellbrock, Claudia; Hurlstone, Adam

doi:10.1084/jem.20160855

Cited by 72 publications

(69 citation statements)

References 62 publications

(110 reference statements)

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“…Interestingly, elevated BRAF expression, MEK1/2 activity and cyclin D1 transcript level in 11_TRAR cells were accompanied with increased level of IL-8. This cytokine has been already implicated in promoting tolerance of melanoma cells to BRAF inhibition, and its receptor C-X-C motif chemokine receptor 2 (CXCR2) was suggested as a potential target in melanoma [80]. In the study of Young et al [80], IL-8 that stimulated the survival of melanoma cells in the presence of BRAF and MEK inhibitors, was released by fibroblasts located in inflammatory niche of the tumor, whereas our study suggests that autocrine signaling is also possible.…”

Section: Discussionmentioning

confidence: 99%

Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

Hartman

Sztiller-Sikorska

Gajos-Michniewicz

et al. 2020

Cells

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The clinical benefit of MAPK pathway inhibition in BRAF-mutant melanoma patients is limited by the development of acquired resistance. Using drug-naïve cell lines derived from tumor specimens, we established a preclinical model of melanoma resistance to vemurafenib or trametinib to provide insight into resistance mechanisms. Dissecting the mechanisms accompanying the development of resistance, we have shown that (i) most of genetic and non-genetic alterations are triggered in a cell line-and/or drug-specific manner; (ii) several changes previously assigned to the development of resistance are induced as the immediate response to the extent measurable at the bulk levels; (iii) reprogramming observed in cross-resistance experiments and growth factor-dependence restricted by the drug presence indicate that phenotypic plasticity of melanoma cells largely contributes to the sustained resistance. Whole-exome sequencing revealed novel genetic alterations, including a frameshift variant of RBMX found exclusively in phospho-AKT high resistant cell lines. There was no similar pattern of phenotypic alterations among eleven resistant cell lines, including expression/activity of crucial regulators, such as MITF, AXL, SOX, and NGFR, which suggests that patient-to-patient variability is richer and more nuanced than previously described. This diversity should be considered during the development of new strategies to circumvent the acquired resistance to targeted therapies.

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Section: Discussionmentioning

confidence: 99%

Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

Hartman

Sztiller-Sikorska

Gajos-Michniewicz

et al. 2020

Cells

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“…Macrophages and fibroblasts can also act together in "inflammatory niches", whereby macrophages secret IL1, which stimulates the production of GRO by fibroblasts. 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).…”

Section: Mapk-reactivation Independent Mechanisms Of Resistance To Brmentioning

confidence: 99%

Overcoming resistance to BRAF inhibitors

Arozarena

Wellbrock

2017

Ann. Transl. Med.

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Abstract:The discovery of activating mutations in the serine/threonine (S/T) kinase BRAF followed by a wave of follow-up research manifested that the MAPK-pathway plays a critical role in melanoma initiation and progression. BRAF and MEK inhibitors produce an unparalleled response rate in melanoma, but it is now clear that most responses are transient, and while some patients show long lasting responses the majority progress within 1 year. In accordance with the key role played by the MAPK-pathway in BRAF mutant melanomas, disease progression is mostly due to the appearance of drug-resistance mechanisms leading to restoration of MAPK-pathway activity. In the present article we will review the development, application and clinical effects of BRAF and MEK inhibitors both, as single agent and in combination in the context of targeted therapy in melanoma. We will then describe the most prominent mechanisms of resistance found in patients progressed on these targeted therapies. Finally we will discuss strategies for further optimizing the use of MAPK inhibitors and will describe the potential of alternative combination therapies to either delay the onset of resistance to MAPK inhibitors or directly target specific mechanisms of resistance to BRAF/ MEK inhibitors.

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“…While MAPK blockade is not designed to specifically increase tumor immunogenicity, increasing numbers of reports suggest that this may indeed be an effect of MAPKi. Tumor‐associated macrophages (TAMs) and CAFs are the major source of IL‐1 in the TME (Young et al, ), and IL‐1 is also secreted from BRAF V600E mutant cells (Khalili et al, ). IL‐1 further stimulated CAFs to upregulate COX‐2, PD‐1 ligands, GROα, and IL‐8 (Khalili et al, ; Young et al, ).…”

Section: The Immune Microenvironment and Resistance To Mapk Blockadementioning

confidence: 99%

“…Tumor‐associated macrophages (TAMs) and CAFs are the major source of IL‐1 in the TME (Young et al, ), and IL‐1 is also secreted from BRAF V600E mutant cells (Khalili et al, ). IL‐1 further stimulated CAFs to upregulate COX‐2, PD‐1 ligands, GROα, and IL‐8 (Khalili et al, ; Young et al, ). Early treatments with BRAFi such as vemurafenib and dabrafenib have also been demonstrated to increase CD4 + and CD8 + T cells (Hong et al, ; Wilmott et al, ), reduce the levels of MDSCs (Schilling et al, ) and Tregs, and restore the maturation of DCs and levels of TNF‐α and IL‐12 (Sumimoto et al, ).…”

Section: The Immune Microenvironment and Resistance To Mapk Blockadementioning

confidence: 99%

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Bad company: Microenvironmentally mediated resistance to targeted therapy in melanoma

Almeida

Douglass

Fane

et al. 2018

Pigment Cell Melanoma Res

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This review will focus on the role of the tumor microenvironment (TME) in the development of drug resistance in melanoma. Resistance to mitogen-activated protein kinase inhibitors (MAPKi) in melanoma is observed months after treatment, a phenomenon that is often attributed to the incredible plasticity of melanoma cells but may also depend on the TME. The TME is unique in its cellular composition-it contains fibroblasts, immune cells, endothelial cells, adipocytes, and among others. In addition, the TME provides "non-homeostatic" levels of oxygen, nutrients (hypoxia and metabolic stress), and extracellular matrix proteins, creating a pro-tumorigenic niche that drives resistance to MAPKi treatment. In this review, we will focus on how changes in the tumor microenvironment regulate MAPKi resistance.

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An adaptive signaling network in melanoma inflammatory niches confers tolerance to MAPK signaling inhibition

Cited by 72 publications

References 62 publications

Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

Overcoming resistance to BRAF inhibitors

Bad company: Microenvironmentally mediated resistance to targeted therapy in melanoma

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