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Structural basis for Smoothened receptor modulation and chemoresistance to anticancer drugs
Antagonists of Smoothened, a class F GPCR involved in the hedgehog pathway, have been developed to treat some cancers. Here Wang et al.report structures of Smoothened in complex with antagonists and an agonist, and describe how mutations may result in resistance to anti-Smoothened treatment.
- Chong Wang
- , Huixian Wu
- & Raymond C. Stevens
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Legumain protease-activated TAT-liposome cargo for targeting tumours and their microenvironment
Legumain is a protease found expressed in tumour cells and may be useful in the specific targeting of chemotherapeutics to tumour cells. Here, the authors design nanoparticles that are loaded with doxorubicin and contain a legumain cleavage site; once the nanoparticles enter tumour cells legumain activity results in the release of doxorubicin.
- Ze Liu
- , Min Xiong
- & Rong Xiang
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| Open Access2q36.3 is associated with prognosis for oestrogen receptor-negative breast cancer patients treated with chemotherapy
Studies have shown that breast cancer prognosis is hereditary. Here the authors show that a genetic variant in CCL20, a chemokine ligand involved in immune response, is significantly associated with breast cancer survival and may therefore represent an important therapeutic or prognostic target.
- Jingmei Li
- , Linda S. Lindström
- & Kamila Czene
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| Open AccessMixed lineage kinases activate MEK independently of RAF to mediate resistance to RAF inhibitors
B-Raf is mutated in many melanomas but treatment of the disease with small molecules targeting the mutant protein often results in tumour resistance. Here, the authors show that mixed lineage kinases (MLK1-4) can reactivate the B-Raf signalling pathway in the presence of inhibitors, resulting in drug resistance.
- Anna A. Marusiak
- , Zoe C. Edwards
- & John Brognard
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Enriched variations in TEKT4 and breast cancer resistance to paclitaxel
Paclitaxel is effective in the treatment of breast cancer but predicting which patients might respond to this drug is of clinical importance. Here, Jiang et al. show that germline mutations in TEKT4, a protein that associates with microtubules, are associated with resistance to paclitaxel therapy.
- Yi-Zhou Jiang
- , Ke-Da Yu
- & Zhi-Ming Shao
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Protein grafting of p53TAD onto a leucine zipper scaffold generates a potent HDM dual inhibitor
The protein levels of the tumour suppressor p53 can be negatively regulated by HDM2, which is an attractive target for cancer therapy. In this study, Lee et al. graft the transactivation domain of p53 onto a scaffold protein and show that this binds to HDM2 and inhibits cancer cell growth in vitro.
- Jung-Hoon Lee
- , Eunji Kang
- & Jae Il Lee
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| Open AccessHarnessing photochemical internalization with dual degradable nanoparticles for combinatorial photo–chemotherapy
Photochemical internalisation is the process by which a laser source activates light sensitive compounds for cellular uptake. Here, the authors combine this technique with photo–chemo degradable polymers for the controlled uptake of chemotherapeutics into cancer cells showing increased cell death.
- George Pasparakis
- , Theodore Manouras
- & Panagiotis Argitis
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| Open AccessPorphyrin–phospholipid liposomes permeabilized by near-infrared light
The delivery of therapeutics using an external trigger is an attractive route for the improvement of targeted disease treatment. Here, the authors have discovered a porphyrin–phospholipid liposome for light-controlled membrane permeabilization and use the system to deliver an anticancer drug in vivo.
- Kevin A. Carter
- , Shuai Shao
- & Jonathan F. Lovell
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Three-layered polyplex micelle as a multifunctional nanocarrier platform for light-induced systemic gene transfer
Light-controlled mechanisms for the delivery of drug molecules to cells is a promising route for non-invasive disease therapy. Here, the authors develop a photosensitive polymeric micelle for light-induced gene transfection and show its effectiveness in vivovia systemic administration.
- Takahiro Nomoto
- , Shigeto Fukushima
- & Kazunori Kataoka
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Selective inhibition of BET bromodomain epigenetic signalling interferes with the bone-associated tumour vicious cycle
A major problem in the treatment of bone tumours and metastases is the vicious cycle between bone tumours and resorption. Here, the authors show that treatment with the BET bromodomain inhibitor JQ1 inhibits osteoblast and osteoclast differentiation, and bone tumour development.
- François Lamoureux
- , Marc Baud’huin
- & Benjamin Ory
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| Open AccessLigand substitutions between ruthenium–cymene compounds can control protein versus DNA targeting and anticancer activity
Ruthenium-cymene-based compounds are investigated as potential anticancer drugs. Here, Adhireksan et al.study two ruthenium-containing compounds with varying cytotoxicity and show that differences in ligand structure may explain their activity and binding to different subcellular targets.
- Zenita Adhireksan
- , Gabriela E. Davey
- & Curt A. Davey
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ATP-triggered anticancer drug delivery
Nanoparticles can deliver drugs to tumours but improvements in selectively targeting tumour cells are required. Here, Mo et al. develop nanocarriers that take advantage of high ATP levels in tumour cells and show that these nanoparticles encapsulating the chemotherapeutic doxorubicin can inhibit tumour growth in mice.
- Ran Mo
- , Tianyue Jiang
- & Zhen Gu
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| Open AccessInduction of mitochondrial dysfunction as a strategy for targeting tumour cells in metabolically compromised microenvironments
Quiescent sub-populations of cells in tumours are resistant to traditional chemotherapeutics and are responsible for tumour recurrence. Here, Zhang et al. identify a compound that kills quiescent tumour cells in solid tumour tissue by inducing mitochondrial dysfunction.
- Xiaonan Zhang
- , Mårten Fryknäs
- & Stig Linder
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| Open AccessInactivation of the Hippo tumour suppressor pathway by integrin-linked kinase
The Hippo tumour suppressor pathway is inactivated in many cancer types, but how this occurs is unclear. Here, the authors show that integrin-linked kinase (ILK) has a role in inhibiting the Hippo pathway and pharmacological inhibition of ILK reduces the size of tumours in mice.
- Isabel Serrano
- , Paul C. McDonald
- & Shoukat Dedhar
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Selective cancer targeting with prodrugs activated by histone deacetylases and a tumour-associated protease
Selective targeting of cancer cells may improve therapeutic efficacy while reducing adverse effects. Here, Ueki et al.report selective activation of an anticancer drug upon removal of an acetylated lysine group by histone deacetylases and the tumour-associated protease cathepsin L.
- Nobuhide Ueki
- , Siyeon Lee
- & Michael J. Hayman
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| Open AccessAngiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels
Hyaluronan is a component of the tumour extracellular matrix. Here, Chauhan et al. show that hyaluronan increases blood pressure in collagen-rich tumours by compressing vessel walls, and that reducing the level of hyaluranon with an angiotensin II inhibitor increases blood flow and drug penetrance in tumours.
- Vikash P. Chauhan
- , John D. Martin
- & Rakesh K. Jain
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| Open AccessTargeting BIG3–PHB2 interaction to overcome tamoxifen resistance in breast cancer cells
Oestrogen receptor-α (ERα) signalling has a role in breast cancer drug resistance. Here, the authors report a synthetic peptide that disrupts the interaction between the signalling molecules BIG3 and PHB2, and thereby suppresses tamoxifen resistance.
- Tetsuro Yoshimaru
- , Masato Komatsu
- & Toyomasa Katagiri
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Non-Darwinian dynamics in therapy-induced cancer drug resistance
Many different factors contribute to the acquisition of drug resistance in cancer cells. Using single-cell analyses of leukaemia cells, the authors here provide evidence for an inductive mode of resistance, where cells express MDR1 in response to drug exposure, rather than selection of pre-existing, partially resistant cells.
- Angela Oliveira Pisco
- , Amy Brock
- & Sui Huang
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| Open AccessATG5 is induced by DNA-damaging agents and promotes mitotic catastrophe independent of autophagy
The protein ATG5 is known to be involved in the formation of autophagosomes. Here, Maskey et al. identify a new role of ATG5 in response to drug-induced DNA damage whereby ATG5 translocates to the nucleus, leading to chromosome misalignment and mitotic catastrophe.
- Dipak Maskey
- , Shida Yousefi
- & Hans-Uwe Simon
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| Open AccessRetinoic acid receptor alpha is associated with tamoxifen resistance in breast cancer
Many patients with breast cancer develop resistance to the drug tamoxifen and relapse. Here Johansson et al. identify the nuclear receptor retinoic acid receptor alpha (RARA) as a marker of tamoxifen resistance and show that RARA expression correlates negatively with relapse-free survival of patients.
- Henrik J. Johansson
- , Betzabe C. Sanchez
- & Janne Lehtiö
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Tumour PDGF-BB expression levels determine dual effects of anti-PDGF drugs on vascular remodelling and metastasis
Anti-cancer drugs inhibiting platelet-derived growth factor (PDGF) can either promote or inhibit tumour growth and metastasis. Here, Hosaka et al.ascribe this dual effect of anti-PDGF drugs to the production of the angiogenic ligand PDGF-BB by tumours, which is shown to regulate PDGFR-β signalling in pericytes.
- Kayoko Hosaka
- , Yunlong Yang
- & Yihai Cao
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A small molecule modulates Jumonji histone demethylase activity and selectively inhibits cancer growth
Epigenetic regulators are promising targets for cancer drugs, as they can modulate a broad range of transcriptional networks simultaneously. Here, the authors identify an inhibitor of Jumonji-family histone demethylases and show that it selectively kills cancer cells in mouse tumour models.
- Lei Wang
- , Jianjun Chang
- & Elisabeth D. Martinez
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Model-based rational design of an oncolytic virus with improved therapeutic potential
Oncolytic viruses can serve as self-replicating anticancer agents. Le Bœuf et al. combine synthetic modelling and molecular biology approaches to create a virus with enhanced oncolytic activity in vitro and in vivodue to its expression of an interferon antagonist.
- Fabrice Le Bœuf
- , Cory Batenchuk
- & John C. Bell
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| Open AccessDrug-induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin
Anthracycline-based drugs can kill cancer cells by inhibiting topoisomerase II and promoting DNA double-strand breaks. Pang et al. show that anthracyclines also induce eviction of histones from open chromatin regions and, in doing so, modulate DNA repair and apoptosis in human cancer cells.
- Baoxu Pang
- , Xiaohang Qiao
- & Jacques Neefjes
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Loss of TRPM2 function protects against irradiation-induced salivary gland dysfunction
A debilitating side effect of radiotherapy in patients with head and neck cancers is xerostomia as a result of salivary gland dysfunction. Here Liu et al. show that activation of the calcium channel TRPM2 in salivary gland cells contributes to irradiation-induced loss of salivary fluid secretion.
- Xibao Liu
- , Ana Cotrim
- & Indu Ambudkar
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MicroRNA-30c inhibits human breast tumour chemotherapy resistance by regulating TWF1 and IL-11
The role of microRNAs in chemotherapy resistance remains to be elucidated. Bockhorn et al.report that microRNA-30c, a human breast tumour prognostic marker, has a key role by targeting the epithelial-to-mesenchymal transition promoter twinfilin 1 and downstream interleukin-11 expression.
- Jessica Bockhorn
- , Rachel Dalton
- & Huiping Liu
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Delivery of chemotherapeutic drugs in tumour cell-derived microparticles
Microparticles are small vesicular structures that are shed from cellular plasma membranes. Tang and colleagues show that cells treated with chemotherapeutic drugs produce drug-containing microparticles, which can be used as anticancer agents in mice.
- Ke Tang
- , Yi Zhang
- & Bo Huang
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| Open AccessCancer cells that survive radiation therapy acquire HIF-1 activity and translocate towards tumour blood vessels
Radiotherapy is used to treat many cancers but radiation-resistant cells can result in recurrence of the tumour. Here, Harada and colleagues develop a method to track cells that persist after radiation treatment and show that the cells acquire transcriptional activity of HIF-1 and move towards blood vessels.
- Hiroshi Harada
- , Masahiro Inoue
- & Masahiro Hiraoka
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Melanoma whole-exome sequencing identifies V600EB-RAF amplification-mediated acquired B-RAF inhibitor resistance
B-RAF is mutated in a large proportion of melanomas, and the first small molecule inhibitor has recently been approved for melanoma treatment. Here, by exome sequencing melanoma samples, Shi and colleagues show that B-RAF is amplified in tumours that have acquired resistance to the B-RAF inhibitor vemurafenib.
- Hubing Shi
- , Gatien Moriceau
- & Roger S. Lo
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| Open AccessAn intrinsically labile α-helix abutting the BCL9-binding site of β-catenin is required for its inhibition by carnosic acid
β-Catenin can be oncogenic but finding inhibitors has been a challenge. Here, five compounds are identified, which attenuate transcriptional β-catenin outputs in colorectal cancer cells, and the response to one of them is shown to require an intrinsically labile α-helix next to the BCL9-binding site in β-catenin.
- Marc de la Roche
- , Trevor J. Rutherford
- & Mariann Bienz