Quantitative proteomics and phosphoproteomics on serial tumor biopsies from a sorafenib-treated HCC patient

Dazert, Eva; Colombi, Marco; Boldanova, Tujana; Moes, Suzette; Adametz, David; Quagliata, Luca; Röth, Volker; Terracciano, Luigi; Heim, Markus H.; Jenoe, Paul; Hall, Michael N.

doi:10.1073/pnas.1523434113

Cited by 64 publications

(49 citation statements)

References 53 publications

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“…Therefore, the tumor cells become more motile and insensitive to antitumor drugs, including sorafenib [45][46][47] . In HCC, different studies have demonstrated that sorafenib resistance mechanisms may involve EMT [45,48] . In a study conducted by van Malenstein and colleagues [45] , five resistant human liver cell lines were developed through long-term exposure to sorafenib.…”

Section: Epithelial-mesenchymal Transition and Sorafenib Resistancementioning

confidence: 99%

New knowledge of the mechanisms of sorafenib resistance in liver cancer

et al. 2017

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Sorafenib is an oral multikinase inhibitor that suppresses tumor cell proliferation and angiogenesis and promotes tumor cell apoptosis. It was approved by the FDA for the treatment of advanced renal cell carcinoma in 2006, and as a unique target drug for advanced hepatocellular carcinoma (HCC) in 2007. Sorafenib can significantly extend the median survival time of patients but only by 3-5 months. Moreover, it is associated with serious adverse side effects, and drug resistance often develops. Therefore, it is of great importance to explore the mechanisms underlying sorafenib resistance and to develop individualized therapeutic strategies for coping with these problems. Recent studies have revealed that in addition to the primary resistance, several mechanisms are underlying the acquired resistance to sorafenib, such as crosstalk involving PI3K/Akt and JAK-STAT pathways, the activation of hypoxia-inducible pathways, and epithelial-mesenchymal transition. Here, we briefly describe the function of sorafenib, its clinical application, and the molecular mechanisms for drug resistance, especially for HCC patients.

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Section: Epithelial-mesenchymal Transition and Sorafenib Resistancementioning

confidence: 99%

New knowledge of the mechanisms of sorafenib resistance in liver cancer

et al. 2017

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“…In this study, we achieved deep-scale multi-omics profiling of core needle biopsy material obtained in a clinical setting using the combined, integrative, tissue-sparing "BioText" approach described in the manuscript and applied this optimized microscaling methodology to a small cohort of breast 14,35,36 or off-line SCX fractionation combined with a super-SILAC approach quantified ~2,000-5,000 proteins and ~3800 phosphorylation sites per core. Importantly, none of these prior studies carried out genomic analyses on the same set of samples.…”

Section: Discussionmentioning

confidence: 99%

Microscaled Proteogenomic Methods for Precision Oncology

Satpathy

Jaehnig

Krug

et al. 2019

Preprint

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and MJE: Matthew.Ellis@bcm.edu Running title: Microscaled Proteogenomic Methods for Precision Oncology Satpathy et al., Microscaled Proteogenomic Methods for Precision Oncology 2 AbstractCancer proteogenomics integrates genomics, transcriptomics and mass spectrometry (MS)-based proteomics to gain insights into cancer biology and treatment efficacy. A proteogenomics approach was therefore developed for frozen core biopsies using tissue-sparing specimen processing with a "microscaled" proteomics workflow. For technical proof-of-principle, biopsies from ERBB2 positive breast cancers before and 48-72 hours after the first dose of neoadjuvant trastuzumabbased chemotherapy were analyzed. ERBB2 protein and phosphosite levels, as well as mTOR target phosphosites, were significantly more suppressed upon treatment in cases associated with pathological complete response, suggesting MS-based pharmacodynamics is achievable. Furthermore, integrated analyses indicated potential causes of treatment resistance including the absence of ERBB2 amplification (false-ERBB2 positive) and insufficient ERBB2 activity for therapeutic sensitivity despite ERBB2 amplification (pseudo-ERBB2 positive). Candidate resistance features in true-ERBB2+ cases, including androgen receptor signaling, mucin expression and an inactive immune microenvironment were observed. Thus, proteogenomic analysis of needle core biopsies is feasible and clinical utility should be investigated. enriched PDX (WHIM) models with ERBB2 protein expression. B. MUC1 immunohistochemistry (IHC) of WHIM8, WHIM35 and BCN1369.

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“…A recent study to explore the mechanisms of sorafenib resistance in human patients used proteomic analysis of HCC tumor before and during sorafenib therapy to show that the HCC tumor proteome exhibited a relatively higher level of glycolytic enzymes during sorafenib treatment. However, it is unclear whether these changes are due to sorafenib therapy or tumor progression 24 .…”

Section: Discussionmentioning

confidence: 99%

Sorafenib and 2-Deoxyglucose Synergistically Inhibit Proliferation of Both Sorafenib-Sensitive and -Resistant HCC Cells by Inhibiting ATP Production

Reyes

Wani²,

Ghoshal³

et al. 2017

gene expr

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Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths globally1,2. Sorafenib is the only first-line systemic drug for advanced HCC, but it has very limited survival benefits because patients treated with sorafenib either suffer from side effects or show disease progression after initial response. Thus, there is an urgent need to develop novel strategies for first-line and second-line therapy. The association between sorafenib resistance and glycolysis prompted us to screen several drugs with known anti-glycolytic activity to identify those that will sensitize cells to sorafenib. We demonstrate that the combination of glycolytic inhibitor 2-deoxy-D-glucose (2DG) and sorafenib drastically inhibits viability of sorafenib sensitive and resistant cells. However, the combination of other anti-glycolytic drugs like lonidamine, gossypol, 3-bromopyruvate and imatinib with sorafenib does not show synergistic effect. Cell cycle analysis revealed that the combination of 2DG and sorafenib induced cell cycle arrest at G0/G1. Mechanistic investigation suggests that the cell-cycle arrest is due to depletion of cellular ATP that activates AMP-activated protein kinase (AMPK), which, in turn, inhibits mammalian target of rapamycin (mTOR) to induce cell cycle arrest. This study provides strong evidence for the therapeutic potential of the combination of sorafenib and 2-deoxyglucose for HCC.

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Quantitative proteomics and phosphoproteomics on serial tumor biopsies from a sorafenib-treated HCC patient

Cited by 64 publications

References 53 publications

New knowledge of the mechanisms of sorafenib resistance in liver cancer

New knowledge of the mechanisms of sorafenib resistance in liver cancer

Microscaled Proteogenomic Methods for Precision Oncology

Sorafenib and 2-Deoxyglucose Synergistically Inhibit Proliferation of Both Sorafenib-Sensitive and -Resistant HCC Cells by Inhibiting ATP Production

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