The Dual EGFR/HER2 Inhibitor Lapatinib Synergistically Enhances the Antitumor Activity of the Histone Deacetylase Inhibitor Panobinostat in Colorectal Cancer Models

LaBonte, Melissa J.; Wilson, Peter M.; Fazzone, William; Russell, Jared; Louie, Stan G.; El-Khoueiry, Anthony B.; Lenz, Heinz‐Josef; Ladner, Robert D.

doi:10.1158/0008-5472.can-10-2430

Cited by 81 publications

(62 citation statements)

References 47 publications

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“…Our preliminary data using combinations of geldanamycin and the EGFR inhibitor lapatinib (Fig. 6) confirm earlier work that the drug combination is more effective than either drug alone but more work is required to establish if this concept can be generalized (47). A further pharmacologically interesting outcome of this proteomic study is the observation that certain signaling pathways (e.g.…”

Section: Hsp90 Regulated Proteome In Different Cellsupporting

confidence: 83%

Systematic Identification of the HSP90 Regulated Proteome

Gholami

Küster

2012

Molecular & Cellular Proteomics

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HSP90 is a central player in the folding and maturation of many proteins. More than two hundred HSP90 clients have been identified by classical biochemical techniques including important signaling proteins with high relevance to human cancer pathways. HSP90 inhibition has thus become an attractive therapeutic concept and multiple molecules are currently in clinical trials. It is therefore of fundamental biological and medical importance to identify, ideally, all HSP90 clients and HSP90 regulated proteins. To this end, we have taken a global and a chemical proteomic approach in geldanamycin treated cancer cell lines using stable isotope labeling with amino acids in cell culture and quantitative mass spectrometry. We identified >6200 proteins in four different human cell lines and ϳ1600 proteins showed significant regulation upon drug treatment. Gene ontology and pathway/network analysis revealed common and cell-type specific regulatory effects with strong connections to unfolded protein binding and protein kinase activity. Of the 288 identified protein kinases, 98 were downregulated upon geldanamycin treatment including >50 kinases not formerly known to be regulated by HSP90. Protein turn-over measurements using pulsed stable isotope labeling with amino acids in cell culture showed that protein down-regulation by HSP90 inhibition correlates with protein half-life in many cases. Protein kinases show significantly shorter half lives than other proteins highlighting both challenges and opportunities for HSP90 inhibition in cancer therapy. The proteomic responses of the HSP90 drugs geldanamycin and PU-H71 were highly similar suggesting that both drugs work by similar molecular mechanisms. Using HSP90 immunoprecipitation, we validated several kinases (AXL, DDR1, TRIO) and other signaling proteins (BIRC6, ISG15, FLII), as novel clients of HSP90. Taken together, our study broadly defines the cellular proteome response to HSP90 inhibition and provides a rich resource for further investigation relevant for the treatment of cancer. Molecular &

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Section: Hsp90 Regulated Proteome In Different Cellsupporting

confidence: 83%

Systematic Identification of the HSP90 Regulated Proteome

Gholami

Küster

2012

Molecular & Cellular Proteomics

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“…Thus, our results further reinforce the importance of extending the mutation screening tests to the less frequent hotspot mutations such as codon 146 or 61 [5,22], which could determine the EGF-response going from signal transduction to the global acetylome of tumor cells. Indeed, the acetylation/deacetylation process is involved in the modulation of the EGFresponse in experimental and clinical CRC studies [15]. However, how the mutational status of KRAS can affect the acetylome of CRC is so far not known.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, deacetylase inhibitors have emerged as potential anti-tumor agents by increasing hyperacetylation of both histones and nonhistone proteins [13]. Furthermore, some reports describe the interplay between KDAC inhibitors and the RAS-ERK signaling cascade in cell lines exhibiting different mutational status in KRAS, BRAF or PI3KCA [14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

152 EGF-induced acetylation of heterogeneous nuclear ribonucleoproteins is dependent on KRAS mutational status in colorectal cancer cells

Roda¹,

Castillo²,

Telechea³

et al. 2015

European Journal of Cancer

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“…BT-474 cells were seeded in glass-bottom dishes at the density of 1×10 4 per dish. After 24 h and 5 min of preincubation with PBS, cells were treated for 30 min with 100 μg/mL (referred to the concentration of lapatinib herein) coumarin-6 loaded LTNPs in Hank's balanced salt solution.…”

Section: Intracellular Tracking Of Ltnpmentioning

confidence: 99%

“…Lapatinib (Tykerb, GlaxoSmithKline) is a dual tyrosine inhibitor of EGFR and HER2 that was approved by the US FDA for the treatment of HER2-positive breast cancer and has also showed positive results on many other cancers [4][5][6] . However, the poor water solubility of lapatinib restricted its clinical outcome.…”

Section: Introductionmentioning

confidence: 99%

Lapatinib-incorporated lipoprotein-like nanoparticles: preparation and a proposed breast cancer-targeting mechanism

Zhang

Ruan

et al. 2014

Acta Pharmacol Sin

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Aim: Lapatinib is a dual inhibitor of EGFR and human epidermal growth factor receptor 2 (HER2), and used to treat advanced breast cancer. To overcome its poor water solubility, we constructed lapatinib-incorporated lipoprotein-like nanoparticles (LTNPs), and evaluated the particle characteristics and possible anti-breast cancer mechanisms. Methods: LTNPs (lapatinib bound to albumin as a core, and egg yolk lecithin forming a lipid corona) were prepared. The particle characteristics were investigated using transmission electron microscopy (TEM) and atomic force microscopy (AFM). The uptake and subcellular localization of LTNPs, as well as the effects of LTNPs on cell cycle were examined in BT-474 human breast cancer cells in vitro. Mice bearing BT-474 subcutaneous xenograft were intravenously injected with coumarin-6 loaded LTNPs (30 mg/kg) to study the targeting mechanisms in vivo. Results: The LTNPs particles were generally spherical but flexible under TEM and AFM, and approximately 62.1 nm in size with a zeta potential of 22.80 mV. In BT-474 cells, uptake of LTNPs was mediated by endosomes through energy-dependent endocytosis involving clathrin-dependent pinocytosis and macropinocytosis, and they could effectively escape from endosomes to the cytoplasm. Treatment of BT-474 cells with LTNPs (20 μg/mL) induced a significant cell arrest at G 0 /G 1 phase compared with the same concentration of lapatinib suspension. In mice bearing BT-474 xenograft, intravenously injected LTNPs was found to target and accumulate in tumors, and colocalized with HER2 and SPRAC (secreted protein, acidic and rich in cysteine). Conclusion: LTNPs can be taken up into breast cancer cells through specific pathways in vitro, and targeted to breast cancer xenograft in vivo via enhanced permeability and retention effect and SPARC.

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The Dual EGFR/HER2 Inhibitor Lapatinib Synergistically Enhances the Antitumor Activity of the Histone Deacetylase Inhibitor Panobinostat in Colorectal Cancer Models

Cited by 81 publications

References 47 publications

Systematic Identification of the HSP90 Regulated Proteome

Systematic Identification of the HSP90 Regulated Proteome

152 EGF-induced acetylation of heterogeneous nuclear ribonucleoproteins is dependent on KRAS mutational status in colorectal cancer cells

Lapatinib-incorporated lipoprotein-like nanoparticles: preparation and a proposed breast cancer-targeting mechanism

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