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Wnt5A Enhances Resistance of Melanoma Cells to Targeted BRAF Inhibitors

ABSTRACT: About half of all melanomas harbor a constitutively active mutant BRAFV600E/K kinase that can be selectively inhibited by targeted BRAF inhibitors (BRAFi). While patients treated with BRAFi initially exhibit measurable clinical improvement, the majority of patients eventually develop drug resistance and relapse. We observe significant elevation of WNT5A in a subset of tumors from patients exhibiting disease progression on BRAFi therapy. WNT5A transcript and protein are also elevated in BRAFi-resistant melanoma cell lines generated by long-term in vitro treatment with BRAFi. RNAi-mediated reduction in levels of endogenous WNT5A in melanoma decreases cell growth, increases apoptosis in response to BRAFi challenge, and decreases the activity of pro-survival AKT signaling. Overexpression of WNT5A conversely promotes melanoma growth and tumorigenesis and activates AKT signaling. Similar to WNT5A knockdown, knockdown of the WNT receptors FZD7 and RYK inhibits growth, sensitizes melanoma cells to BRAFi, and reduces AKT activation. Together, these findings suggest that chronic BRAF inhibition elevates WNT5A expression, which then acts through FZD7 and RYK to promote AKT signaling, leading to increased growth and therapeutic resistance. Increased WNT5A expression in BRAFi-resistant melanomas also correlates with an associated transcriptional signature, which identifies potential therapeutic targets to reduce clinical resistance to BRAFi.

ORGANISM(S): Homo sapiens

PROVIDER: GSE55583 | GEO | 2014/03/06

SECONDARY ACCESSION(S): PRJNA240147

REPOSITORIES: GEO

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Wnt5A Enhances Resistance of Melanoma Cells to Targeted BRAF Inhibitors

Project description:About half of all melanomas harbor a constitutively active mutant BRAFV600E/K kinase that can be selectively inhibited by targeted BRAF inhibitors (BRAFi). While patients treated with BRAFi initially exhibit measurable clinical improvement, the majority of patients eventually develop drug resistance and relapse. We observe significant elevation of WNT5A in a subset of tumors from patients exhibiting disease progression on BRAFi therapy. WNT5A transcript and protein are also elevated in BRAFi-resistant melanoma cell lines generated by long-term in vitro treatment with BRAFi. RNAi-mediated reduction in levels of endogenous WNT5A in melanoma decreases cell growth, increases apoptosis in response to BRAFi challenge, and decreases the activity of pro-survival AKT signaling. Overexpression of WNT5A conversely promotes melanoma growth and tumorigenesis and activates AKT signaling. Similar to WNT5A knockdown, knockdown of the WNT receptors FZD7 and RYK inhibits growth, sensitizes melanoma cells to BRAFi, and reduces AKT activation. Together, these findings suggest that chronic BRAF inhibition elevates WNT5A expression, which then acts through FZD7 and RYK to promote AKT signaling, leading to increased growth and therapeutic resistance. Increased WNT5A expression in BRAFi-resistant melanomas also correlates with an associated transcriptional signature, which identifies potential therapeutic targets to reduce clinical resistance to BRAFi. Expression of WNT5A-correlated genes was compared in melanoma cell lines generated to be resistant to PLX4032 and the their associated naïve parental line Basal expression of the WNT5A-correlated genes was also measured in experiments comparing each naïve line to a mixed reference pool containing equal amounts of 47 melanoma cell lines.

2014-03-06 | E-GEOD-55583 | biostudies-arrayexpress

Molecular changes induced in melanoma cells by stromal cells and anti-BRAF therapy.

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The CoREST Repressor Complex Mediates Phenotype Switching and Therapy Resistance in Melanoma

Project description:Virtually all patients with BRAF-mutant melanoma develop resistance to MAPK inhibitors largely through non-mutational events. Although the epigenetic landscape is shown to be altered in therapy-resistant melanomas and other cancers, a specific targetable epigenetic mechanism has not been validated to date. Here, we evaluate the CoREST repressor complex and the recently developed bivalent inhibitor, corin, within the context of melanoma phenotype plasticity and therapeutic resistance. We find that CoREST is a critical mediator of the major distinct melanoma phenotypes and that corin treatment of melanoma cells leads to phenotype reprogramming. Global assessment of transcript and chromatin changes conferred by corin reveals specific effects on histone marks connected to EMT-associated transcription factors and the dual-specificity phosphatases (DUSPs). Remarkably, treatment of BRAF inhibitor (BRAFi)-resistant melanomas with corin promotes resensitization to BRAFi therapy. DUSP1 is consistently downregulated in BRAFi-resistant melanomas which is reversed by corin treatment and associated with inhibition of p38 MAPK activity and resensitization to BRAFi therapies. Moreover, this activity can be recapitulated by the p38 MAPK inhibitor, BIRB 796. These findings identify the CoREST repressor complex as a central mediator of melanoma phenotype plasticity and resistance to targeted therapy and suggest that CoREST inhibitors may prove beneficial to patients with BRAFi- resistant melanoma.

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The CoREST Repressor Complex Mediates Phenotype Switching and Therapy Resistance in Melanoma [ChIP-seq]

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Expression data for melanoma cell lines with different resistance to SBI-0640756

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Neratinib, a pan ERBB/HER inhibitor, restores sensitivity of PTEN-null, BRAFV600E melanoma to BRAF/MEK inhibition

Project description:Approximately 50% of melanomas harbor an activating BRAFV600E mutation. Standard of care involves a combination of inhibitors targeting mutant BRAF and MEK1/2, the substrate for BRAF in the MAPK pathway. PTEN loss of function mutations occur in 40% of BRAFV600E melanomas, resulting in increased PI3K/AKT activity that enhances resistance to BRAF/MEK combination inhibitor therapy. To compare the response of PTEN null to PTEN wild type cells in an isogenic background, CRISPR was used to knock out PTEN a melanoma cell line that harbors a BRAFV600E mutation. RNA sequencing and functional kinome analysis revealed the loss of PTEN led to an induction of FOXD3 and an increase in expression of the FOXD3 target gene, ERBB3/HER3. Inhibition of BRAF and MEK1/2 in PTEN null, BRAFV600Ecells dramatically induced expression of ERBB3/HER3 relative to wild type cells. A synergy screen of epigenetic modifiers and kinase inhibitors in combination with BRAFi/MEKi identified the pan ERBB/HER inhibitor, neratinib, as reversing the resistance observed in PTEN null, BRAFV600Ecells. The findings indicate that PTEN null BRAFV600E melanoma exhibits increased reliance on ERBB/HER signaling when treated with clinically approved BRAFi/MEKi combinations. Future studies are warranted to test neratinib reversal of resistance in patient melanomas expressing ERBB3/HER3 in combination with its dimerization partner ERBB2/HER2.

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Molecular changes induced in melanoma cells by stromal cells and anti-BRAF therapy.

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