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Surprisal Analysis of Patient-Specific Signaling Networks in TNBC

ABSTRACT: The present study sought to combine surprisal analysis, utilizing systems-level data to predict unbalanced processes in each patient tumor, with quantitative analysis of tyrosine phosphorylation mediated signaling networks to identify potential therapeutic targets and therapeutic combinations in TNBC patient-derived xenografts.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Breast Cancer Cell

DISEASE(S): Breast Cancer

SUBMITTER: Jason Conage-Pough

LAB HEAD: Forest Michael White

PROVIDER: PXD042640 | Pride | 2025-01-14

REPOSITORIES: Pride

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			Action	DRS
	JCP_051422_AC2_pY_BR98_erl_tax_9plex.mzML	Mzml
	JCP_051422_AC2_pY_BR98_erl_tax_9plex.mzid.gz	Mzid
	JCP_051422_AC2_pY_BR98_erl_tax_9plex.raw	Raw
	JCP_051422_AC4_pY_PDX11_erl_ag_18plex.mzML	Mzml
	JCP_051422_AC4_pY_PDX11_erl_ag_18plex.mzid.gz	Mzid

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Publications

Patient-specific signaling signatures predict optimal therapeutic combinations for triple negative breast cancer.

Alkhatib Heba H Conage-Pough Jason J Roy Chowdhury Sangita S Shian Denen D Zaid Deema D Rubinstein Ariel M AM Sonnenblick Amir A Peretz-Yablonsky Tamar T Granit Avital A Carmon Einat E Kohale Ishwar N IN Boughey Judy C JC Goetz Matthew P MP Wang Liewei L White Forest M FM Kravchenko-Balasha Nataly N

Molecular cancer 20240116 1

Triple negative breast cancer (TNBC) is a heterogeneous group of tumors which lack estrogen receptor, progesterone receptor, and HER2 expression. Targeted therapies have limited success in treating TNBC, thus a strategy enabling effective targeted combinations is an unmet need. To tackle these challenges and discover individualized targeted combination therapies for TNBC, we integrated phosphoproteomic analysis of altered signaling networks with patient-specific signaling signature (PaSSS) analy ...[more]

PMID: 38229082

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Src Family Kinases as potential therapeutic targets for chemotherapy-resistant triple negative breast cancer

Project description:Here we quantified tyrosine phosphorylation (pTyr) mediated signaling networks in chemotherapy sensitive (CS) and resistant (CR) TNBC patient derived xenografts (PDX) to gain novel therapeutic insights. We identified Src Family Kinases (SFKs) as potential therapeutic targets in CR TNBC PDXs. Additionally, we performed pTyr analysis on tumor specimens derived from TNBC patients and observed lower prevalence of SFK driven tumors.

2022-10-13 | PXD034154 | Pride

AR heterogeneity in TNBC MDA-MB-453 cells

Project description:Triple-negative breast cancer (TNBC) is aggressive and difficult, and few targeted therapies are available to treat this patient population. The androgen receptor (AR) has emerged as a potential target in breast cancer. Newer generation AR inhibitors, such as Seviteronel (Sevi), are unique in their ability to inhibit AR both directly and by blocking upstream androgen synthesis. The purpose of this study was to investigate the pre-clinical activity of Sevi in TNBC and further explore the effectiveness of targeting both androgen biosynthesis and AR activity in combination with other downstream acting agents. AR overexpressing (AR+) TNBC cell lines, xenografts and androgen responsive patient-derived xenograft (PDX) models were using to show how effectively Sevi inhibits AR activity and cell/tumor proliferation. Single cell RNA-sequencing of the AR+ cell line MDA-MB-453 illustrated heterogeneity in AR levels and identified cell cycle pathway activation in ARHigh versus ARLow expressing cells. Combination treatment with the cell cycle CDK4/6 inhibitor abemaciclib and Sevi showed synergy in AR+ TNBC cells and increased effectiveness, compared to each drug alone, in an AR+ TNBC xenograft model. While cell cycle inhibitors have been approved for use in hormone-receptor positive breast cancer, our studies suggest that these drugs may be equally effective in AR+ TNBC cells, especially when combined with AR antagonists. Implications. These data suggest that targeting AR signaling at multiple points throughout the pathway may be an effective was to treat patients with AR+ TNBC.

2020-06-12 | GSE152315 | GEO

Expression data of patient-derived triple negative breast cancer xenograft tumors

Project description:Triple negative breast cancer (TNBC) is an aggressive subtype that lack targeted clinical therapies. In addition, TNBC is heterogeneous and was recently further sub-classified into seven TNBC subtypes that displayed unique gene expression patterns. To develop therapeutic treatment regimens, we established seven patient-derived xenograft models from TNBC tumors. These xenograft models not only retained the histology and clinical markers of the corresponding patient tumors, but also bearing the same mutations and deletions identified in the patient tumors. Moreover, as part of evaluation of these models, we performed microarrays on the xenograft tumors to assess their TNBC subtypes. After obtaining IRB-approved informed written patient consent, breast cancer tissues were obtained fresh from Stanford Hospital and transplanted into the number 2 mammary fat pads of female NOD SCID mice (NOD.CB17-Prkdcscid/J, Jackson Laboratory West, Sacramento, CA, USA). Mice were maintained in pathogen-free animal housing. The established xenografts were subsequently passaged from mouse to mouse. Xenograft tumor tissues were frozen on dry ice for RNA isolation and microarray analysis.

2014-03-21 | E-GEOD-47079 | biostudies-arrayexpress

Characterization of WSD-0922 Signaling

Project description:The present pre-clinicial study sought to evaluate the novel EGFR inhibitor WSD-0922. We employed flank and orthotopic patient derived xenograft (PDX) models to characterize WSD-0922 and compare its therapeutic efficacy to erlotinib, a potent EGFR inhibitor that failed to provide clinical benefit for GBM patients. We utilized phosphotyrosine mass spectrometry analyses to measure the impact of each drug on receptor activity and cellular signaling networks.

2023-06-21 | PXD032974 | Pride

TNBC response to CDK4/6 inhibitors plus RANKL inhibitors

Project description:CDK4/6i alone have proven to be largely ineffective in TNBC, even in the presence of functional retinoblastoma protein (pRB). In this study, we investigated the role of the RANK pathway in the response to CDK4/6i in pRB-proficient TNBC. Transcriptomic analysis of xenografts revealed that combining CDK4/6i with RANKLi more effectively arrested the cell cycle.

2025-05-20 | GSE277615 | GEO

DAPK3 modulates migration and invasion of triple negative breast cancers

Project description:A mass spectrometry (MS)-based kinase inhibitor pulldown assay (KIPA) was applied to analyze 16 patient-derived xenografts (PDXs) leading to the discovery that Death-Associated Protein Kinase 3 (DAPK3) is significantly and specifically overexpressed in triple negative breast cancer (TNBC). Validation studies confirmed the enrichment of DAPK3 at the protein level, independent of RNA expression, in both TNBC cell lines and tumors. Genomic knockout of DAPK3 in TNBC cell lines inhibited in vitro migration and invasion, along with downregulation of an epithelial-mesenchymal transition (EMT) signature. The kinase and leucine-zipper domains within DAPK3 were shown by mutational analysis to be essential for functionality. Notably, DAPK3 was found to inhibit the levels of desmoplakin (DSP), a crucial component of the desmosome complex, thereby explaining TNBC migration and invasion effects. Further exploration with immunoprecipitation-mass spectrometry (IP-MS) identified Leucine-zipper protein 1 (LUZP1) as a strong binding partner of DAPK3, engaging in a leucine-zipper-domain-mediated interaction that protects DAPK3 from degradation. Thus, DAPK3 emerges as a novel regulator of EMT components in TNBC.

2025-05-06 | PXD049187 | Pride

Targeting LCK utilizing a selective inhibitor as a therapeutic approach in Cholangiocarcinoma

Project description:There is an unmet need to develop novel, effective medical therapies for cholangiocarcinoma (CCA). The Hippo pathway effector, YAP, is oncogenic in cholangiocarcinoma; however, attempts to therapeutically target YAP in vivo have been unsuccessful thus far. Recently, we described a novel role for the Src-family kinase LCK in activating YAP through tyrosine phosphorylation. This led to the hypothesis that LCK may be a viable therapeutic target in cholangiocarcinoma to regulate YAP activity. NTRC 0652-0 is a novel tyrosine kinase inhibitor with specificity for LCK. NTRC 0652-0 demonstrated selectivity for LCK inhibition in vitro and in cholangiocarcinoma cells. NTRC 0652-0 treatment led to decreased tyrosine phosphorylation of YAP, inhibition of its activity and apoptotic cell death in cholangiocarcinoma cell lines, associated with inhibition of MCL1 expression - consider rephrasing this last part to make the sentence read better. The extent of sensitivity of patient-derived organoids to NTRC 0652-0 correlated with basal YAP tyrosine phosphorylation and suppression of YAP co-transcriptional activity following drug treatment. In a patient-derived xenograft CCA model bearing an FGFR2 fusion, daily oral treatment with NTRC 0652-0 produced stable tumor drug levels, acceptable toxicity, and significantly decreased tumor growth. Overall, a novel LCK inhibitor, NTRC 0652-0, inhibited YAP signaling and demonstrated preclinical efficacy in CCA cell-lines, organoids, and patient derived xenograft models.

2025-05-06 | PXD026925 | Pride

Identification of Nuclear Export Inhibitor-Based Combination Therapies in Preclinical Models of Triple-Negative Breast Cancer

Project description:An estimated 284,000 Americans will be diagnosed with breast cancer in 2021. Of these individuals, 15-20% will be diagnosed with basal-like triple-negative breast cancer (TNBC), which is known to be highly metastatic. Chemotherapy is standard of care for TNBC patients, but acquired chemoresistance is a common clinical problem. There is currently a lack of alternative, targeted treatment strategies for TNBC; this study sought to identify novel therapeutic combinations to treat basal-like TNBCs. For these studies, a set of four human basal-like TNBC cell lines was utilized to determine the cytotoxicity profile of 1,363 unique clinically-used drugs. Ten promising therapeutic candidates were identified, and synergism studies were performed in vitro. Two drug combinations that included KPT-330, an XPO1 inhibitor, were synergistic in all four cell lines. In vivo testing of four basal-like patient-derived xenografts identified a combination, KPT-330 and GSK2126458 (a PI3K/mTOR inhibitor), that decreased tumor burden in mice significantly more than monotherapy with either single agent. Bulk and single-cell RNA-sequencing, immunohistochemical studies, and analysis of published genomic datasets found that XPO1 was abundantly expressed in human basal-like TNBC cell lines, patient-derived xenografts, and patient tumor samples; within basal-like patients, XPO1 overexpression was associated with greater rates of metastases. These studies identify a promising new combination therapy for patients with basal-like TNBC.

2021-10-20 | GSE174391 | GEO

ATACseq of TNBC cell lines treated with EZH2i (tazemetostat) and/or AKTi (ipatasertib)

Project description:Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype and has the highest rate of recurrence1. The predominant standard of care for advanced TNBC is systemic chemotherapy with or without immunotherapy, however responses are typically short-lived1,2. Thus, there is an urgent need to develop more effective treatments. PI3K pathway components represent plausible therapeutic targets, as approximately 70% of TNBCs have PIK3CA/AKT1/PTEN alterations3–6. However, unlike hormone receptor-positive tumors, it is still unclear if or how PI3K pathway inhibitors will be effective in triple-negative disease7. Here we identify a promising AKT inhibitor-based therapeutic combination for TNBC. Specifically, we show that AKT inhibitors potently synergize with agents that suppress the histone methyltransferase, EZH2, and promote robust tumor regression in multiple TNBC models in vivo. AKT and EZH2 inhibitors exert these effects by first cooperatively driving basal-like TNBC cells into a more differentiated, luminal-like state, which cannot be effectively induced by either agent alone. Once differentiated, these agents kill TNBCs by hijacking signals that normally drive mammary gland involution. Finally, using machine learning approach, we developed a classifier that can be used for patient selection. Together these findings identify a promising therapeutic strategy for this highly aggressive tumor type and illustrate how deregulated epigenetic enzymes can insulate tumors from oncogenic vulnerabilities. These studies also reveal how developmental tissue-specific cell death pathways may be co-opted for therapeutic benefit.

2024-07-08 | GSE252382 | GEO

Transcriptomes of triple-negative breast cancer (TNBC) cells (SUM159) and non-TNBC cells (HCC1569) that overexpressed JMJD6 were compared

Project description:The expression levels of JMJD6 and its correlation with H2A.XY39ph differed in TNBC and non-TNBC cells. In addition, we have previously shown that H2A.XY39ph levels are positively correlated with tumor size, histological grade and advanced TNM stage in breast cancer. To analyze the role of JMJD6 in regulating the characteristics of different subtypes of breast cancer, the transcriptomes of TNBC cells (SUM159) and non-TNBC cells (HCC1569) that overexpressed JMJD6 were compared. We speculate that JMJD6 overexpression cause autophagy pathway activation in TNBC via enhancing ATG genes expression.

2023-10-01 | E-MTAB-6517 | biostudies-arrayexpress

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