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Kinome profiling of Non-Hodgkin Lymphoma identifies Tyro3 as a therapeutic target in PEL

ABSTRACT: Non-Hodgkin lymphomas (NHL) make up the majority of lymphoma diagnoses and represent a very diverse set of malignancies. We sought to identify kinases uniquely upregulated in different NHL subtypes. Using Multiplexed Inhibitor Bead-mass spectrometry (MIB/MS), we found Tyro3 was uniquely upregulated and important for cell survival in primary effusion lymphoma (PEL), which is a viral lymphoma infected with Kaposi’s sarcoma-associated herpesvirus (KSHV).

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): B Cell, Cell Suspension Culture

DISEASE(S): Lymphoma

SUBMITTER: Jason Wong

LAB HEAD: Blossom Andrea Damania

PROVIDER: PXD012087 | Pride | 2019-07-11

REPOSITORIES: Pride

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			Action	DRS
	tjs150414_Granta_53.raw	Raw
	tjs150414_JVM-2_56.raw	Raw
	tjs150414_Jeko-1_57.raw	Raw
	tjs150414_PrimaryB_52.raw	Raw
	tjs150414_REC-1_55.raw	Raw

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Publications

Kinome profiling of non-Hodgkin lymphoma identifies Tyro3 as a therapeutic target in primary effusion lymphoma.

Wong Jason P JP Stuhlmiller Timothy J TJ Giffin Louise C LC Lin Carolina C Bigi Rachele R Zhao Jichen J Zhang Weihe W Bravo Cruz Ariana G AG Park Steven I SI Earp H Shelton HS Dittmer Dirk P DP Frye Stephen V SV Wang Xiaodong X Johnson Gary L GL Damania Blossom B

Proceedings of the National Academy of Sciences of the United States of America 20190725 33

Non-Hodgkin lymphomas (NHLs) make up the majority of lymphoma diagnoses and represent a very diverse set of malignancies. We sought to identify kinases uniquely up-regulated in different NHL subtypes. Using multiplexed inhibitor bead-mass spectrometry (MIB/MS), we found Tyro3 was uniquely up-regulated and important for cell survival in primary effusion lymphoma (PEL), which is a viral lymphoma infected with Kaposi's sarcoma-associated herpesvirus (KSHV). Tyro3 was also highly expressed in PEL ce ...[more]

PMID: 31346082

Similar Datasets

Kinome profiling of Non-Hodgkin’s lymphoma reveals Tyro3 is important in primary effusion lymphoma survival

Project description:Non-Hodgkin’s lymphomas (NHL) make up the majority of lymphoma diagnoses and represent a very diverse set of malignancies. We sought to identify kinases uniquely upregulated in different NHL subtypes. Using Multiplexed Inhibitor Bead-mass spectrometry (MIB/MS), we found Tyro3 was uniquely upregulated and important for cell survival in primary effusion lymphoma (PEL). We developed an inhibitor against Tyro3 named UNC3810A, which inhibited cell growth in PEL but not in other NHL subtypes. UNC3810A also significantly inhibited tumor progression in a PEL xenograft mouse model compared to the vehicle treated animals. Our data suggests Tyro3 may be a therapeutic target for PEL.

2019-07-10 | GSE114791 | GEO

Kinome profiling in HER2+ breast cancer patients in response to 7 days of HER2-targeting

Project description:Inhibition of the HER2/ERBB2 receptor is a keystone to treating HER2-positive malignancies, particularly breast cancer, but a significant fraction of HER2-positive (HER2+) breast cancers recur or fail to respond. Anti-HER2 monoclonal antibodies, like trastuzumab or pertuzumab, and ATP active site inhibitors like lapatinib, commonly lack durability because of adaptive changes in the tumor leading to resistance. HER2-directed therapy using clinically relevant drugs (trastuzumab with or without lapatinib or pertuzumab) in a 7-day clinical trial (ClinicalTrials.gov Identifier: NCT01875666, LCCC1214) designed to examine early pharmacodynamic response to antibody-based anti-HER2 therapy showed reduced FOXA1 transcription factor expression was coincident with decreased HER2 and HER3 levels, decreased proliferation gene signatures, and increased immune gene signatures. Patient samples from this trial, when sufficient material was available, were also subjected to kinase enrichment using multiplexed kinase inhibitor bead affinity chromatography and LC-MS/MS. Strongly responsive transcriptional responses observed in a subset of patients corresponded to decreased binding of CDK1 and DDR1 by our proteomic approach. Taken together, our results highlight the importance of the immune response to anti-HER2 antibodies and suggests that inhibiting FOXA1-mediated adaptive responses in combination with HER2 targeting is a potential therapeutic strategy.

2021-04-09 | PXD021865 | Pride

Effect of oxygen tension on MMTV-PyMT tumor cell kinome

Project description:Solid tumors are characterized by significantly lower oxygen (O2) levels. Despite this fact, routine preclinical cancer studies are performed under ambient O2 conditions. We have developed an experimental approach that allows us to collect, process and evaluate cancer and non-cancer cells under physioxia (3-5% O2), in such a way that there is very minimal exposure to air. We have shown in previous studies that ambient and physioxic O2 differentially impact relevant cell surface markers and sensitivity to therapy. In this study, our goal was to further explore oxygen-dependent signaling pathway alterations and to determine how these pathways influence response to targeted therapies. Using cells derived from transgenic mouse mammary tumors and healthy primary human breast epithelial cells, we show the impact of ambient air and physioxia on the kinome, with subsequent pathway alterations that mediate the effectiveness of single and combination therapies. Our data emphasize the importance of O2 considerations in preclinical cancer research and drug development.

2024-05-08 | PXD046005 | Pride

Determining the KRAS-regulated kinome in PDAC

Project description:Oncogenic KRAS drives cancer growth by activating diverse signaling networks, not all of which have been fully delineated. We set out to establish a system-wide profile of the KRAS-regulated kinase signaling network (kinome) in KRAS-mutant pancreatic ductal adenocarcinoma (PDAC). We knocked down KRAS expression in a panel of six cell lines, and then applied Multiplexed Inhibitor Bead/Mass Spectrometry (MIB/MS) chemical proteomics to monitor changes in kinase activity and/or expression. We hypothesized that depletion of KRAS would result in downregulation of kinases required for KRAS-mediated transforming activities, and in upregulation of other kinases that could potentially compensate for the deleterious consequences of the loss of KRAS. We identified 15 upregulated and 13 downregulated kinases in common across the panel. In agreement with our hypothesis, all 15 of the upregulated kinases have established roles as cancer drivers (e.g., SRC, TGFBR1, ILK), and pharmacologic inhibition of the upregulated kinase, DDR1, suppressed PDAC growth. Interestingly, 11 of the 13 downregulated kinases have established driver roles in cell cycle progression, particularly in mitosis (e.g., WEE1, Aurora A, PLK1). Consistent with a crucial role for the downregulated kinases in promoting KRAS-driven proliferation, we found that pharmacologic inhibition of WEE1 also suppressed PDAC growth. The unexpected paradoxical activation of ERK upon WEE1 inhibition led us to inhibit both WEE1 and ERK concurrently, which caused further potent growth suppression and enhanced apoptotic death than WEE1 inhibition alone. We conclude that system-wide delineation of the KRAS-regulated kinome can identify potential therapeutic targets for KRAS-mutant pancreatic cancer.

2022-02-17 | PXD025819 | Pride

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

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

2024-04-23 | PXD033921 | Pride

Kinome profiling: cabozantinib treatment in a mouse model of plexiform neurofibroma

Project description:Neurofibromatosis type 1 (NF1) is the most common autosomal dominant disorder, affecting 1 in 3,500 individuals worldwide and predisposing to cancer. Germline mutations in the NF1 gene, encoding the p21Ras GTPase-activating protein (GAP) neurofibromin, are the underlying cause for NF1. Somatic inactivation of the wild type copy of NF1 leads to deregulated Ras signaling. Clinical manifestations are diverse for NF1 patients, but the predominant lesions are plexiform neurofibroma (PNF), arising from the Schwann cell (SC) lineage. While PNF are generally benign, approximately 10% of patients will experience PN progression to highly aggressive malignant peripheral nerve sheath tumors (MPNST) with poor prognosis. There are currently no approved targeted therapies for PNF or MPNST. In this study, we used a conditional mouse model of NF1, test the multi-receptor tyrosine kinase inhibitor, cabozantinib (XL184). Mice were treated with vehicle or with cabozantinib for 3 or 7 days. Tissue was harvested, lysates prepared, and the lysate was used for kinome profiling. From cell lines or tumor tissue, protein lysates are prepared and passed over an affinity matrix consisting of Sepharose beads covalently coupled to a mixture of linker-adapted Type I kinase inhibitors. Kinase capture is reproducible and is a function of affinity for kinases for the immobilized inhibitors, expression level of the kinase, as well as the activation state of the kinase. Following affinity purification, kinases are identified and their multiplexed kinase inhibitor bead binding quantified by mass spectrometry (MIB/MS). Our goal is to identify the kinome changes in NF1 plexiform neurofibroma induced by cabozantinib treatment.

2020-11-19 | PXD019138 | Pride

SOX4 AND SMARCA4 COOPERATIVELY REGULATE PI3K SIGNALING THROUGH TRANSCRIPTIONAL ACTIVATION OF TGFBR2 IN TRIPLE NEGATIVE BREAST CANCER

Project description:Dysregulation of PI3K/Akt signaling is a dominant feature in basal-like or triple-negative breast cancers (TNBC). However, the mechanisms regulating this pathway are largely unknown in this subset of aggressive tumors. Here we demonstrate that the transcription factor SOX4 is a key regulator of PI3K signaling in TNBC. Genomic and proteomic analyses coupled with mechanistic studies identified TGFBR2 as a direct transcriptional target of SOX4 and demonstrated that TGFBR2 is required to mediate SOX4-dependent PI3K signaling. We further report that SOX4 and the SWI/SNF ATPase SMARCA4, which are uniformly overexpressed in basal-like tumors, form a previously unreported complex that is required to maintain an open chromatin conformation at the TGFBR2 regulatory regions in order to mediate TGFBR2 expression and PI3K signaling. Collectively, our findings delineate the mechanism by which SOX4 and SMARCA4 cooperatively regulate PI3K/Akt signaling and suggest that this complex may play an essential role in TNBC genesis and/or progression. Kinase enrichment proteomic analysis was performed using HCC1143 breast cancer cells treated with a control siRNA pool or a pool targeting SOX4 in biological triplicate to evaluate the effects on the functional kinome.

2021-03-03 | PXD022596 | Pride

Clinical Impact of Circulating miR-92a Levels in Non-Hodgkin’s Lymphoma

Project description:To identify the differentially expressed miRs in the plasmas of non-Hodgkin's lymphoma (NHL) patients, we screened NHL samples using microarrays. Experiments were performed with three pooled total RNA isolated from the plasmas of four patients with diffuse large B-cell lymphoma (DLBCL), four patients with follicular lymphoma (FL), and eight control samples.

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Kinome profiling: cabozantinib treatment in a mouse model of plexiform neurofibroma

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