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Effect of PTEN knockout on dabrafenib-trametinib treatment in A375 melanoma cells - replicate 2

ABSTRACT: 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 in the A375 melanoma cell line that harbors a BRAFV600E mutation. Kinome profiling was performed using the parental line and two PTEN KO clones (5 and 11), treated with DMSO, or treated with 100nM dabrafenib and 10nM trametinib for 1 day or for 7 days. PTEN KO cells showed dramatically increased binding of HER3 and AKT3 compared to wild type. The activation of the SOX10-FOXD3-HER3-AKT axis in PTEN KO cells could be targeted with the ERBB/HER inhibitor neratinib.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Steven Angus

LAB HEAD: Steven Angus

PROVIDER: PXD033921 | Pride | 2024-04-23

REPOSITORIES: Pride

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			Action	DRS
	20180924_SPA_MIBs_A375_PTEN_KO_01.raw	Raw
	20180924_SPA_MIBs_A375_PTEN_KO_02.raw	Raw
	20180924_SPA_MIBs_A375_PTEN_KO_03.raw	Raw
	20180924_SPA_MIBs_A375_PTEN_KO_04.raw	Raw
	20180924_SPA_MIBs_A375_PTEN_KO_05.raw	Raw

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Effect of PTEN knockout on dabrafenib-trametinib treatment in A375 melanoma cells - replicate 1

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 in the A375 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 BRAFand MEK1/2 in PTEN null, BRAFV600E cells dramatically induced expression of ERBB3/HER3 relative to wild type cells. A synergy screen of epigenetic modifiers and kinase inhibitors in combination with inhibitors for mutant BRAF/MEK1/2 identified the pan ERBB/HER inhibitor, neratinib, as reversing the resistance observed in PTEN null, BRAFV600E cells. The findings indicate PTEN null BRAFV600E melanoma becomes dependent on ERBB/HER signaling when treated with clinically approved BRAF and MEK inhibitors. Future studies are warranted to test neratinib reversal of resistance in patient melanomas expressing ERBB3/HER3 in combination with its dimerization partner ERBB2/HER2.

2024-04-23 | PXD033866 | Pride

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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RNA-seq melanoma

Project description:Using a chromatin regulator-focused shRNA library, we found that suppression of sex determining region Y-box 10 (SOX10) in melanoma causes resistance to BRAF and MEK inhibitors. To investigate how SOX10 loss leads to drug resistance, we performed transcriptome sequencing (RNAseq) of both parental A375 (Ctrl. PLKO) and A375-SOX10KD (shSOX10-1, shSOX10-2) cells. To ask directly whether SOX10 is involved indrug resistance in BRAF(V600E) melanoma patients, we isolated RNA from paired biopsies from melanoma patients (pre- and post- treatment) , that had gained BRAF or MEK inhibitor resistance . We performed RNAseq analysis to determine changes in transcriptome upon drug resistance. Investigate genes regulated by SOX10 and differntial gene expression between pre- and post-treatment biopsies. We use short hairpin RNA to suppression SOX10 in A375 cells and cells were harvested with trizol reagent for RNA isolation. For paired biopsies (patient samples) we collected the first biopsy before the initiation of treatment and the second biopsy after drug resistance developed. RNA was isolated from FFPE samples and subjected for RNA sequencing.

2014-01-04 | E-GEOD-50535 | biostudies-arrayexpress

Beta-catenin Controls Metastasis in Braf-activated Pten-inactivated Melanomas

Project description:Malignant melanoma is characterized by frequent metastasis, however specific changes that regulate this process have not been clearly delineated. Although it is well known that Wnt signaling is frequently dysregulated in melanoma, the functional implications of this observation are unclear. By modulating beta-catenin levels in a mouse model of melanoma that is based on melanocyte-specific Pten loss and BrafV600E mutation, we demonstrate that beta-catenin is a central mediator of melanoma metastasis to lymph node and lung. In addition to altering metastasis, beta-catenin levels control tumor differentiation and regulate both MAPK/Erk and PI3K/Akt signaling. Highly metastatic tumors with beta-catenin stabilization are very similar to a subset of human melanomas; together these findings establish Wnt signaling as a metastasis regulator in melanoma. MoGene-1_0-st-v1: Four samples total. Two biological replicates of uncultured Pten/Braf murine melanomas and two biological replicates of uncultured Pten/Braf/Bcat-STA murine melanomas. MoEx-1_0-st-v1: Two samples total. Dissociated tumor and FACS-enriched Pten/Braf and Pten/Braf/Bcat-STA murine melanoma.

2011-10-12 | E-GEOD-32907 | biostudies-arrayexpress

Mouse melanoma types with various genotypes

Project description:Only a subset of melanoma patients has evidence for spontaneous T cell infiltration into tumor sites, previously associated with clinical responses. However, the molecular mechanisms explaining absence of a T cell response are not yet defined. Analyses of human melanoma metastases have revealed that T cell signature low tumors show alterations in the Wnt/b-catenin signaling pathway. We utilized an inducible mouse model driven by inducible BrafV600E and PTEN-deletion, with or without active b-catenin (CAT-STA) to test if tumor intrinsic active b-catenin can block anti-tumor immunity. While Braf/PTEN melanomas showed presence of a T cell infiltrate, T cells were nearly completely eliminated in tumors expressing active b-catenin. Adoptive transfer experiments revealed defective T cell priming when tumors expressed active b-catenin. Analysis of the antigen-presenting cell compartment revealed a selective decrease in the CD103+ DC subset within the tumor microenvironment, which could be associated with b-catenin depended inhibition of expression of the chemokine CCL4 within tumor cells. Here we used 3 mice of each genotype BrafV600E/PTEN-/- and BrafV600E/PTEN-/-/Cat-STA and compared their gene-expression profiles. we used 3 mice of each genotype BrafV600E/PTEN-/- and BrafV600E/PTEN-/-/Cat-STA and compared their gene-expression profiles.

2015-02-28 | E-GEOD-63543 | biostudies-arrayexpress

Gene expression profile in melanomas from Pdk1-inactivated BrafV600E::Pten-/- mice

Project description:Gene expression profiling was performed to access the changes in gene expression in melanomas from Pdk1-inactivated Brafv600E::Pten-/- mice. The expression profiles of the BrafV600E::Pten-/-::Pdk1-/- were compared to the BrafV600E::Pten-/-::Pdk+/+ genotypes. The analysis has identified several important signaling pathways in Pdk1-dependent melanomagenesis. Melanoma tumors from the BrafV600E::Pten-/-::Pdk1+/+ and BrafV600E::Pten-/-::Pdk1-/- genotypes were harvested and mRNA from each group was pooled to enable four biologically replicates analysis.

2013-09-17 | E-GEOD-42187 | biostudies-arrayexpress

Gene expression profile in melanomas from Pdk1-inactivated BrafV600E::Pten-/- mice

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Gene expression data from Tyr::CreErT2::BrafV600E Pten F/+ mouse tumors according to defloxing status of Brn2 [cell lines]

Project description:To investigate the mechanism underlying the effect of Brn2-loss we extracted mRNA from Braf-Pten-Brn2-wt, Braf-Pten-Brn2-het, and Braf-Pten-Brn2-hom mouse melanomas and performed microarray-based transcriptome analysis.

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Gene expression data from Tyr::CreErT2::BrafV600E Pten F/+ mouse tumors according to defloxing status of Brn2 [tumors]

2021-04-13 | GSE126524 | GEO

Expression data from BRAFV600E A375 melanoma cells treated with vehicle or vemurafenib

Project description:Vemurafenib is a BRAF inhibitor with specificity for the most common BRAF mutant encountered in melanomas (BRAFV600E). Vemurafenib suppresses the proliferation of BRAF mutant human melanoma cells by suppressing downstream activation of the MEK/ERK mitogen activated protein kinases. We used microarrays to examine the transcriptional response of a vemurafenib-sensitive BRAFV600E human melanoma cell line (A375) to vemurafenib in order to further delineate the mechanisms by which BRAFV600E drives cell proliferation and energy metabolism in human melanoma.

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