An <i>In Vivo</i> Functional Screen Identifies JNK Signaling As a Modulator of Chemotherapeutic Response in Breast Cancer

Ashenden, Matthew; Weverwijk, Antoinette van; Murugaesu, Nirupa; Fearns, Antony; Campbell, James; Gao, Qiong; Iravani, Marjan; Isacke, Clare M.

doi:10.1158/1535-7163.mct-16-0731

Cited by 19 publications

(20 citation statements)

References 46 publications

(61 reference statements)

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“…Furthermore, they suggest that these inhibitors might be candidate therapeutics for cancers similar to MCF7 in lineage (i.e., breast) or genetic features (e.g., estrogen receptor positive). Indeed, CHEK1 inhibition is a promising therapeutic direction in the treatment of breast and ovarian cancers ( Bryant et al, 2014 ), and JNK signaling has an important, but poorly understood, role in breast cancer ( Ashenden et al, 2017 ).…”

Section: Resultsmentioning

confidence: 99%

A Library of Phosphoproteomic and Chromatin Signatures for Characterizing Cellular Responses to Drug Perturbations

et al. 2018

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SUMMARYAlthough the value of proteomics has been demonstrated, cost and scale are typically prohibitive, and gene expression profiling remains dominant for characterizing cellular responses to perturbations. However, high-throughput sentinel assays provide an opportunity for proteomics to contribute at a meaningful scale. We present a systematic library resource (90 drugs 3 6 cell lines) of proteomic signatures that measure changes in the reduced-representation phosphoproteome (P100) and changes in epigenetic marks on histones (GCP). A majority of these drugs elicited reproducible signatures, but notable cell line- and assay-specific differences were observed. Using the “connectivity” framework, we compared signatures across cell types and integrated data across assays, including a transcriptional assay (L1000). Consistent connectivity among cell types revealed cellular responses that transcended lineage, and consistent connectivity among assays revealed unexpected associations between drugs. We further leveraged the resource against public data to formulate hypotheses for treatment of multiple myeloma and acute lymphocytic leukemia. This resource is publicly available at https://clue.io/proteomics.

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Section: Resultsmentioning

confidence: 99%

A Library of Phosphoproteomic and Chromatin Signatures for Characterizing Cellular Responses to Drug Perturbations

et al. 2018

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“…95 Inhibiting JNK impairs proapoptotic signaling and promotes breast cancer resistance to anthracyclines in mouse and human models. 96 Perona and Sanchez-Perez 79 proposed that JNK pathways may promote cell cycle entry, thereby increasing the sensitivity of cells to anticancer drugs. The proposed mechanism of JNK-induced chemoresistance is illustrated in Figure 2.…”

Section: Jnk Signaling Plays a Role In Cancer Chemoresistancementioning

confidence: 99%

JNK signaling in cancer cell survival

et al. 2019

Medicinal Research Reviews

220

146

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c‐Jun N‐terminal kinase (JNK) is involved in cancer cell apoptosis; however, emerging evidence indicates that this Janus signaling promotes cancer cell survival. JNK acts synergistically with NF‐κB, JAK/STAT, and other signaling molecules to exert a survival function. JNK positively regulates autophagy to counteract apoptosis, and its effect on autophagy is related to the development of chemotherapeutic resistance. The prosurvival effect of JNK may involve an immune evasion mechanism mediated by transforming growth factor‐β, toll‐like receptors, interferon‐γ, and autophagy, as well as compensatory JNK‐dependent cell proliferation. The present review focuses on recent advances in understanding the prosurvival function of JNK and its role in tumor development and chemoresistance, including a comprehensive analysis of the molecular mechanisms underlying JNK‐mediated cancer cell survival. There is a focus on the specific “Yin and Yang” functions of JNK1 and JNK2 in the regulation of cancer cell survival. We highlight recent advances in our knowledge of the roles of JNK in cancer cell survival, which may provide insight into the distinct functions of JNK in cancer and its potential for cancer therapy.

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“…As previously detailed 48 Glucose uptake assay. 1-5x10 4 cells were seeded in 100 µL culture medium containing 10% FBS into a 96-well plate and incubated for 24 hours at 37°C.…”

Section: In Vivo Shrna Screenmentioning

confidence: 99%

Metabolic adaptability in metastatic breast cancer by AKR1B10-dependent balancing of glycolysis and fatty acid oxidation

Weverwijk

Koundouros

Iravani

et al. 2018

Preprint

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Running title: Regulation of fatty acid oxidation during breast cancer metastasis Keywords: breast cancer metastasis, metabolic regulation, AKR1B10, fatty acid oxidation, lung metastasis Abstract The different stages of the metastatic cascade present distinct metabolic challenges to tumour cells and an altered tumour metabolism associated with successful metastatic colonisation provides a therapeutic vulnerability in disseminated disease. We identify the aldo-keto reductase AKR1B10 as a metastasis enhancer that has little impact on primary tumour growth or dissemination but promotes effective tumour growth in secondary sites and, in human disease, is associated with an increased risk of distant metastatic relapse. AKR1B10 High tumour cells have reduced glycolytic capacity and dependency on glucose as fuel source but increased utilisation of fatty acid oxidation. Conversely, in both 3D tumour spheroid assays and in vivo metastasis assays, inhibition of fatty acid oxidation blocks AKR1B10 Highenhanced metastatic colonisation with no impact on AKR1B10 Low cells. Finally, mechanistic analysis supports a model in which AKR1B10 serves to limit the toxic side effects of oxidative stress thereby sustaining fatty acid oxidation in metabolically challenging metastatic environments.A defining characteristic of primary tumour cells is an ability to alter their metabolism, which provides the energy and metabolites required to sustain survival in nutrient and oxygen limiting conditions. In disseminating tumour cells this need for an altered metabolism becomes more acute, as cells have to avoid anoikis-mediated cell death in the circulation and face the challenge of surviving at the metastatic site before establishment of a productive metastatic colony. Moreover, different metastatic sites pose distinct metabolic challenges to the tumour cell 1,2 . In breast cancers, these altered metabolic dependencies are now being defined but the molecular mechanisms regulating this metabolic adaptability have yet to be identified.Here we report the analysis of a syngeneic in vivo RNAi screen to identify putative metastasis enhancers. Among the top hits from the screen was the aldo-keto

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An In Vivo Functional Screen Identifies JNK Signaling As a Modulator of Chemotherapeutic Response in Breast Cancer

Cited by 19 publications

References 46 publications

A Library of Phosphoproteomic and Chromatin Signatures for Characterizing Cellular Responses to Drug Perturbations

A Library of Phosphoproteomic and Chromatin Signatures for Characterizing Cellular Responses to Drug Perturbations

JNK signaling in cancer cell survival

Metabolic adaptability in metastatic breast cancer by AKR1B10-dependent balancing of glycolysis and fatty acid oxidation

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