Amuvatinib has cytotoxic effects against NRAS-mutant melanoma but not BRAF-mutant melanoma

Fedorenko, Inna V.; Fang, Bin; Koomen, John M.; Gibney, Geoffrey T.; Smalley, Keiran S.M.

doi:10.1097/cmr.0000000000000103

Cited by 16 publications

(15 citation statements)

References 20 publications

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“…Probably the most significant consequence of Axl upregulation in carcinomas of the skin is increased migratory ability of cells. In melanoma, Axl is associated with NRAS mutations compared to BRAF mutations, and is inversely correlated with the expression of the microphthalmia-associated transcription factor (MITF) [ 210 – 213 ]. Correlation studies also reveal the association of Axl with cell motility, invasion, and interactions with the surrounding microenvironment, and treatment with R428, a selective Axl inhibitor, reduces migration and invasion of cells [ 213 ].…”

Section: Tissue and Cell Type-specific Roles For Axlmentioning

confidence: 99%

“…Another report found that Axl and Mer are expressed in a mutually exclusive manner, where Mer is associated with BRAF mutations and Axl is associated with NRAS mutations [ 215 ]. Accordingly, treatment of NRAS-mutant melanoma cell lines with an inhibitor targeting multiple kinases including Axl, leads to growth arrest and apoptosis [ 210 ]. This drug has no effect in BRAS-mutant cell lines which lack Axl expression.…”

Section: Tissue and Cell Type-specific Roles For Axlmentioning

confidence: 99%

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Axl as a mediator of cellular growth and survival

2014

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The control of cellular growth and proliferation is key to the maintenance of homeostasis. Survival, proliferation, and arrest are regulated, in part, by Growth Arrest Specific 6 (Gas6) through binding to members of the TAM receptor tyrosine kinase family. Activation of the TAM receptors leads to downstream signaling through common kinases, but the exact mechanism within each cellular context varies and remains to be completely elucidated. Deregulation of the TAM family, due to its central role in mediating cellular proliferation, has been implicated in multiple diseases. Axl was cloned as the first TAM receptor in a search for genes involved in the progression of chronic to acute-phase leukemia, and has since been established as playing a critical role in the progression of cancer. The oncogenic nature of Axl is demonstrated through its activation of signaling pathways involved in proliferation, migration, inhibition of apoptosis, and therapeutic resistance. Despite its recent discovery, significant progress has been made in the development of effective clinical therapeutics targeting Axl. In order to accurately define the role of Axl in normal and diseased processes, it must be analyzed in a cell type-specific context.

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Section: Tissue and Cell Type-specific Roles For Axlmentioning

confidence: 99%

Section: Tissue and Cell Type-specific Roles For Axlmentioning

confidence: 99%

Axl as a mediator of cellular growth and survival

2014

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“…The exact compliment of RTKs responsible for driving innate or acquired resistance to small molecule kinase inhibitors in melanoma remains to be determined, and targeting these modalities remains a significant clinical challenge. Amuvatinib (MP-470), which inhibits MET, KIT, PDGFRA, and AXL, was shown to attenuate NRAS mutant melanoma cell growth and induce apoptosis in vitro [50]; however, MP-470 has not been assessed clinically. The small molecule MET, RET, KIT, FLT-1, FLT-3, FLT-4, TIE2, AXL, PDGFR-β kinase inhibitor XL-184 (cabozantinib) was assessed in a phase II randomized trial and demonstrated tumor regression in 55% of melanoma patients (5% objective response rate), with no correlation noted between response and BRAF status [51].…”

Section: Discussionmentioning

confidence: 99%

Resistance mechanisms to genetic suppression of mutant NRAS in melanoma

et al. 2017

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Targeted therapies have revolutionized cancer care but the development of resistance remains a challenge in the clinic. To identify rational targets for combination strategies, we used an established melanoma mouse model and selected for resistant tumors following genetic suppression of NRAS expression. Complete tumor regression was observed in all mice but 40% of tumors recurred. Analysis of resistant tumors revealed that the most common mechanism of resistance was overexpression and activation of receptor tyrosine kinases (RTKs). Interestingly, the most commonly overexpressed RTK was Met and inhibition of Met overcame NRAS resistance in this context. Analysis of NRAS mutant human melanoma cells revealed enhanced efficacy of cytotoxicity with combined RTK and MEK inhibition. In this study, we establish the importance of adaptive RTK signaling in the escape of NRAS mutant melanoma from inhibition of RAS and provide the rationale for combined blockade of RAS and RTK signaling in this context.

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“…(46) Spheroids were treated with DMSO control or increasing concentrations of PF573228 for 72 hours, then stained with Calcein AM for viability at 30 minutes to 1 hour (Thermo Fisher, Waltham, MA), and imaged immediately.…”

Section: Methodsmentioning

confidence: 99%

Activity-Based Protein Profiling Shows Heterogeneous Signaling Adaptations to BRAF Inhibition

et al. 2016

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Patients with BRAF V600E mutant melanoma are typically treated with targeted BRAF kinase inhibitors, such as vemurafenib and dabrafenib. Although these drugs are initially effective, they are not curative. Most of the focus to date has been upon genetic mechanisms of acquired resistance; therefore, we must better understand the global signaling adaptations that mediate escape from BRAF inhibition. In the current study, we have used activity-based protein profiling (ABPP) with ATP-analogue probes to enrich kinases and other enzyme classes that contribute to BRAF inhibitor (BRAFi) resistance in four paired isogenic BRAFi-naïve/resistant cell line models. Our analysis showed these cell line models, which differ in their PTEN status, have considerable heterogeneity in their kinase ATP probe uptake in comparing naïve cells and adaptations to chronic drug exposure. A number of kinases including FAK1, SLK and TAOK2 had increased ATP probe uptake in BRAFi resistant cells, while KHS1 (M4K5) and BRAF had decreased ATP probe uptake in the BRAFi-resistant cells. Gene ontology (GO) enrichment analysis revealed BRAFi resistance is associated with a significant enhancement in ATP probe uptake in proteins implicated in cytoskeletal organization and adhesion, and decreases in ATP probe uptake in proteins associated with cell metabolic processes. The ABPP approach was able to identify key phenotypic mediators critical for each BRAFi resistant cell line. Together, these data show that common phenotypic adaptations to BRAF inhibition can be mediated through very different signaling networks, suggesting considerable redundancy within the signaling of BRAF mutant melanoma cells.

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Amuvatinib has cytotoxic effects against NRAS-mutant melanoma but not BRAF-mutant melanoma

Cited by 16 publications

References 20 publications

Axl as a mediator of cellular growth and survival

Axl as a mediator of cellular growth and survival

Resistance mechanisms to genetic suppression of mutant NRAS in melanoma

Activity-Based Protein Profiling Shows Heterogeneous Signaling Adaptations to BRAF Inhibition

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