Precision medicine driven by cancer systems biology

Filipp, Fabian V.

doi:10.1007/s10555-017-9662-4

Cited by 40 publications

(38 citation statements)

References 144 publications

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“…Although surgically curable at early stages, late-stage melanoma is difficult to treat due to genomic tumor variability and therapy resistance (3). The constitutive activation of the mitogen-activated protein kinase pathway is frequently altered in melanoma and initially responsive to targeted treatment (4). However, disease relapse and tumor progression impedes long-term survival (5).…”

Section: Introductionmentioning

confidence: 99%

Concurrent Targeting of Glutaminolysis and Metabotropic Glutamate Receptor 1 (GRM1) Reduces Glutamate Bioavailability in GRM1+ Melanoma

et al. 2019

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Aberrant glutamatergic signaling has been implicated in altered metabolic activity in many cancer types, including malignant melanoma. Previously, we have illustrated the role of metabotropic glutamate receptor 1 (GRM1) in neoplastic transformation of melanocytes in vitro and spontaneous metastatic melanoma in vivo. In this study, we showed that autocrine stimulation constitutively activates the GRM1 receptor and its downstream mitogenic signaling. GRM1activated (GRM1 þ) melanomas exhibited significantly increased expression of glutaminase (GLS), which catalyzes the first step in the conversion of glutamine to glutamate. In cultured GRM1 þ melanoma cell lines, CB-839, a potent, selective, and orally bioavailable inhibitor of GLS, suppressed cell proliferation, while riluzole, an inhibitor of glutamate release, promoted apoptotic cell death in vitro and in vivo. Combined treatment with CB-839 and riluzole treatment proved to be superior to single-agent treatment, restricting glutamate bioavailability and leading to effective suppression of tumor cell proliferation in vitro and tumor progression in vivo. Hyperactivation of GRM1 in malignant melanoma is an oncogenic driver, which acts independently of canonical melanoma proto-oncogenes, BRAF or NRAS. Overall, these results indicate that expression of GRM1 promotes a metabolic phenotype that supports increased glutamate production and autocrine glutamatergic signaling, which can be pharmacologically targeted by decreasing glutamate bioavailability and the GLS-dependent glutamine to glutamate conversion. Significance: These findings demonstrate that targeting glutaminolytic glutamate bioavailability is an effective therapeutic strategy for GRM1-activated tumors.

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Section: Introductionmentioning

confidence: 99%

Concurrent Targeting of Glutaminolysis and Metabotropic Glutamate Receptor 1 (GRM1) Reduces Glutamate Bioavailability in GRM1+ Melanoma

et al. 2019

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“…The discovery of the specific role of KDM3A in the interplay between a tissue specific steroid receptor transcription factor and metabolic signaling provides a foundation for rational design of combination approaches where metabolic, epigenetic, and hormone-deprivation therapies may synergize. Our integrated multi-platform analysis reveals a complex molecular landscape of epigenomic and transcriptomic cooperation in cancer, providing avenues for precision medicine 34 . A close teamwork of the transcriptional and epigenomic machinery was discovered, in which one component opens the chromatin, another recognizes gene-specific DNA motifs, and others scaffold between histones, cofactors, and the transcriptional complex.…”

Section: Resultsmentioning

confidence: 99%

A network of epigenomic and transcriptional cooperation encompassing an epigenomic master regulator in cancer

Wilson

Filipp

2018

Preprint

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Coordinatedexperiments focused on transcriptional responses and chromatin states are wellequipped to capture different epigenomic and transcriptomic levels governing the circuitry of a regulatory network. We propose a workflow for the genome-wide identification of epigenomic and transcriptional cooperation to elucidate transcriptional networks in cancer. Gene promoter annotation in combination with network analysis and sequence-resolution of enriched transcriptional motifs in epigenomic data reveals transcription factor families that act synergistically with epigenomic master regulators. A close teamwork of the transcriptional and epigenomic machinery was discovered. The network is tightly connected and includes the histone lysine demethylase KDM3A, basic helix-loop-helix factors MYC, HIF1A, and SREBF1, as well as differentiation factors AP1, MYOD1, SP1, MEIS1, ZEB1 and ELK1. In such a cooperation network, one component opens the chromatin, another one recognizes gene-specific DNA motifs, others scaffold between histones, cofactors, and the transcriptional complex. In cancer, due to the ability to team up with transcription factors, epigenetic factors concert mitogenic and metabolic gene networks, claiming the role of a cancer master regulators or epioncogenes.Specific histone modification patterns are commonly associated with open or closed chromatin states, and are linked to distinct biological outcomes by transcriptional activation or repression. Disruption of patterns of histone modifications is associated with loss of proliferative control and cancer. There is tremendous therapeutic potential in understanding and targeting histone modification pathways. Thus, investigating cooperation of chromatin remodelers and the transcriptional machinery is not only important for elucidating fundamental mechanisms of chromatin regulation, but also necessary for the design of targeted therapeutics.

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“…Genomic sequencing has facilitated the understanding of acquired resistance mechanisms to MAPKis [14,35,36,15,37,16,38]. Detected genetic aberrations included mutations in NRAS, MAPK1/2, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA, Gene ID: 5290), and phosphatase and tensin homolog (PTEN, Gene ID: 5728).…”

Section: Discussionmentioning

confidence: 99%

Systems biology analysis of mitogen activated protein kinase inhibitor resistance in malignant melanoma

Zecena

Tveit

Wang

et al. 2017

Preprint

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Kinase inhibition in the mitogen activated protein kinase (MAPK) pathway is a standard therapy for cancer patients with activating BRAF mutations. However, the anti-tumorigenic effect and clinical benefit are only transient, and tumors are prone to treatment resistance and relapse. To elucidate mechanistic insights into drug resistance, we have established an in vitro cellular model of MAPK inhibitor resistance in malignant melanoma. The cellular model evolved in response to clinical dosage of BRAF inhibitor, vemurafenib, PLX4032. We conducted transcriptomic expression profiling using RNA-Seq and RT-qPCR arrays. Pathways of melanogenesis, MAPK signaling, cell cycle, and metabolism were significantly enriched among the set of differentially expressed genes of vemurafenib-resistant cells vs control. The underlying mechanism of treatment resistance and pathway rewiring based on non-genomic adaptation was validated in two distinct melanoma models, SK-MEL-28 and A375. Both cell lines have activating BRAF mutations and display metastatic potential. Downregulation of tumor suppressors and negative MAPK regulators, dual specific phosphatases, reengages mitogenic signaling. Upregulation of growth factors or cytokine receptors triggers signaling pathways circumventing BRAF blockage. Changes in amino acid and one-carbon metabolism support cellular proliferation despite MAPK inhibitor treatment. In addition, an upregulation of pigmentation in inhibitor resistant melanoma cells was observed. Cellular pathways utilized during inhibitor resistance promoted melanogenesis, a pathway which partially overlaps with MAPK signaling. Upstream regulator analysis suggested gene expression changes of forkhead box and hypoxia inducible factor family transcription factors. The established cellular models offer mechanistic insight into cellular changes and therapeutic targets under inhibitor resistance in malignant melanoma. At a systems biology level, the MAPK pathway undergoes major rewiring while acquiring inhibitor resistance. The outcome of this transcriptional plasticity is selection for a set of transcriptional master regulators, which circumvent upstream targeted kinases and provide alternative routes of mitogenic activation. A fine-woven network of redundant signals maintains similar effector genes allowing for tumor cell survival and malignant progression in therapy resistant cancer.

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Precision medicine driven by cancer systems biology

Cited by 40 publications

References 144 publications

Concurrent Targeting of Glutaminolysis and Metabotropic Glutamate Receptor 1 (GRM1) Reduces Glutamate Bioavailability in GRM1+ Melanoma

Concurrent Targeting of Glutaminolysis and Metabotropic Glutamate Receptor 1 (GRM1) Reduces Glutamate Bioavailability in GRM1+ Melanoma

A network of epigenomic and transcriptional cooperation encompassing an epigenomic master regulator in cancer

Systems biology analysis of mitogen activated protein kinase inhibitor resistance in malignant melanoma

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