Featured
-
-
Article
| Open AccessStructure-based classification predicts drug response in EGFR-mutant NSCLC
Structural classification of mutations in the epidermal growth factor receptor causing non-small cell lung cancer is a better predictor of patient outcomes following drug treatment than traditional exon-based classification.
- Jacqulyne P. Robichaux
- , Xiuning Le
- & John V. Heymach
-
Article |
Cycling cancer persister cells arise from lineages with distinct programs
Lineage tracing by barcoding of individual cells using a lentivirus library shows that cycling and non-cycling drug-tolerant persister cells in cancer arise from different lineages with distinct transcriptional and metabolic programs.
- Yaara Oren
- , Michael Tsabar
- & Aviv Regev
-
Article |
EGFR activation limits the response of liver cancer to lenvatinib
EGFR inhibition and lenvatinib treatment of liver cancer cells in vitro and in in vivo mouse models has potent anti-proliferative effects, and lenvatinib plus gefitinib treatment of 12 patients with advanced liver cancer resulted in meaningful clinical responses.
- Haojie Jin
- , Yaoping Shi
- & René Bernards
-
Article |
Structural basis of antifolate recognition and transport by PCFT
Cryo-electron microscopy structures of PCFT in a substrate-free state and bound to the antifolate drug pemetrexed provide insights into how this protein recognizes folates and mediates their transport into cells.
- Joanne L. Parker
- , Justin C. Deme
- & Simon Newstead
-
Article |
DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer
DHO dehydrogenase regulates ferroptosis by preventing mitochondrial lipid peroxidation and its inhibition suppresses growth in tumours with low levels of GPX4.
- Chao Mao
- , Xiaoguang Liu
- & Boyi Gan
-
Article |
Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity
A CRISPR–Cas9 screen of chromatin regulators in mouse tumour models treated with immune checkpoint blockade identifies SETDB1 as an epigenetic checkpoint protein that suppresses tumour-intrinsic immunogenicity.
- Gabriel K. Griffin
- , Jingyi Wu
- & Bradley E. Bernstein
-
Article |
Chromothripsis drives the evolution of gene amplification in cancer
Chromothripsis—a process during which chromosomes are ‘shattered’—drives the evolution of gene amplification and subsequent drug resistance in cancer cells.
- Ofer Shoshani
- , Simon F. Brunner
- & Don W. Cleveland
-
Article |
Small-molecule inhibitors of human mitochondrial DNA transcription
Inhibitors of mitochondrial transcription that target human mitochondrial RNA polymerase provide a chemical biology tool for studying the role of mitochondrial DNA expression in a wide range of pathologies.
- Nina A. Bonekamp
- , Bradley Peter
- & Nils-Göran Larsson
-
Article |
Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer
Inhibiting the PCSK9 protein, a regulator of cholesterol metabolism, enhances immune checkpoint therapy in mouse models of cancer, in a manner that depends on the regulation of antigen-presenting MHC I molecules.
- Xinjian Liu
- , Xuhui Bao
- & Chuan-Yuan Li
-
Article |
Epigenetic therapy induces transcription of inverted SINEs and ADAR1 dependency
Inverted-repeat Alu elements are the main source of drug-induced immunogenic double-stranded RNAs, which are destabilized by the RNA deaminase ADAR1, thereby limiting activation of the immune response.
- Parinaz Mehdipour
- , Sajid A. Marhon
- & Daniel D. De Carvalho
-
Article |
Structural basis for the action of the drug trametinib at KSR-bound MEK
Crystal structures of the MEK kinase bound to the scaffold protein KSR and various MEK inhibitors, including the anti-cancer drug trametinib, reveal the molecular and functional mechanisms behind MEK inhibition.
- Zaigham M. Khan
- , Alexander M. Real
- & Arvin C. Dar
-
Article |
TRIM37 controls cancer-specific vulnerability to PLK4 inhibition
Acentrosomal assembly of the mitotic spindle upon inhibition of the PLK4 protein is shown to depend on the ubiquitin ligase TRIM37, with implications for the use of PLK4 inhibitors to treat neuroblastoma and breast cancer.
- Franz Meitinger
- , Midori Ohta
- & Karen Oegema
-
Article |
Serine restriction alters sphingolipid diversity to constrain tumour growth
In xenograft tumour models in mice, modulation of dietary serine, serine palmitoyltransferase or phosphoglycerate dehydrogenase activity enables control of the endogenous synthesis of deoxysphingolipids, sensitizing the tumours to metabolic stress and slowing their progression.
- Thangaselvam Muthusamy
- , Thekla Cordes
- & Christian M. Metallo
-
Article |
An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma
Results of an exploratory interim analysis from a phase I trial show that an RNA vaccine targeted towards four melanoma-associated antigens produces durable objective responses in patients with melanoma that are accompanied by strong CD4+ and CD8+ T-cell immunity.
- Ugur Sahin
- , Petra Oehm
- & Özlem Türeci
-
Article |
Mechanisms and therapeutic implications of hypermutation in gliomas
Temozolomide therapy seems to lead to mismatch repair deficiency and hypermutation in gliomas, but not to an increase in response to immunotherapy.
- Mehdi Touat
- , Yvonne Y. Li
- & Keith L. Ligon
-
Review Article |
Dietary modifications for enhanced cancer therapy
- Naama Kanarek
- , Boryana Petrova
- & David M. Sabatini
-
Article |
Peripheral T cell expansion predicts tumour infiltration and clinical response
Large-scale single-cell sequencing of RNA and T cell receptors in samples from patients with cancer shows clonotypic expansion of effector-like T cells not only in tumour tissue but also in normal adjacent tissues and peripheral blood, which associates with clinical response to cancer immunotherapy.
- Thomas D. Wu
- , Shravan Madireddi
- & Jane L. Grogan
-
Article |
Epigenetic therapy inhibits metastases by disrupting premetastatic niches
In mouse models of pulmonary metastasis, adjuvant epigenetic therapy targeting myeloid-derived suppressor cells disrupts the premetastatic microenvironment after resection of primary tumours and inhibits the dissemination of residual tumour cells.
- Zhihao Lu
- , Jianling Zou
- & Malcolm V. Brock
-
Article |
Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer
ABBV-744, a selective inhibitor of the BD2 domains of BET family proteins, is effective against prostate cancer in mouse xenograft models, with lower toxicities than the dual-bromodomain BET inhibitor ABBV-075.
- Emily J. Faivre
- , Keith F. McDaniel
- & Yu Shen
-
Article |
B cells and tertiary lymphoid structures promote immunotherapy response
Multiomic profiling of several cohorts of patients treated with immune checkpoint blockade highlights the presence and potential role of B cells and tertiary lymphoid structures in promoting therapy response.
- Beth A. Helmink
- , Sangeetha M. Reddy
- & Jennifer A. Wargo
-
Article |
B cells are associated with survival and immunotherapy response in sarcoma
Immune profiling of the tumour microenvironment of soft-tissue sarcoma identifies a group of patients with high levels of B-cell infiltration and tertiary lymphoid structures that have improved survival and a high response rate to immune checkpoint blockade therapy.
- Florent Petitprez
- , Aurélien de Reyniès
- & Wolf H. Fridman
-
Article |
Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition
Populations of KRAS(G12C)-mutant cancer cells can rapidly bypass the effects of treatment with KRAS(G12C) inhibitors because a subset of cells escapes drug-induced quiescence by producing new KRAS(G12C) that is maintained in its active, drug-insensitive state.
- Jenny Y. Xue
- , Yulei Zhao
- & Piro Lito
-
Review Article |
A view on drug resistance in cancer
A review of drug resistance in cancer analyses each biological determinant of resistance separately and discusses existing and new therapeutic strategies to combat the problem as a whole.
- Neil Vasan
- , José Baselga
- & David M. Hyman
-
Article |
The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity
Treatment of KRASG12C-mutant cancer cells with the KRAS(G12C) inhibitor AMG 510 leads to durable response in mice, and anti-tumour activity in patients suggests that AMG 510 could be effective in patients for whom treatments are currently lacking.
- Jude Canon
- , Karen Rex
- & J. Russell Lipford
-
Article |
MHC-II neoantigens shape tumour immunity and response to immunotherapy
In a mouse tumour model, immunotherapy-induced rejection of tumour cells requires presentation of both MHC class I and MHC class II antigens, which activate CD4+ and CD8+ T cells, respectively.
- Elise Alspach
- , Danielle M. Lussier
- & Robert D. Schreiber
-
Review Article |
Harnessing innate immunity in cancer therapy
The authors review recent developments in our understanding of the antitumour effects of the innate immune system and how this system could be harnessed in the clinic.
- Olivier Demaria
- , Stéphanie Cornen
- & Eric Vivier
-
Letter |
Inducing and exploiting vulnerabilities for the treatment of liver cancer
CDC7 inhibition selectively induces senescence in hepatocellular carcinoma cells with TP53 mutations, which enables the selective apoptotic cell death of these senescent cells using inhibitors of mTOR signalling.
- Cun Wang
- , Serena Vegna
- & René Bernards
-
Letter |
The Drug Rediscovery protocol facilitates the expanded use of existing anticancer drugs
Clinical benefit was observed in 34% of a cohort of 215 patients with cancer who received treatment with anticancer drugs outside of their approved label, in the Drug Rediscovery protocol trial.
- D. L. van der Velden
- , L. R. Hoes
- & E. E. Voest
-
Article |
Glutamatergic synaptic input to glioma cells drives brain tumour progression
Neurons form glutamatergic synapses with glioma cells in mice and humans, and inhibition of AMPA receptors reduces glioma cell invasion and growth.
- Varun Venkataramani
- , Dimitar Ivanov Tanev
- & Thomas Kuner
-
Letter |
Tumour lineage shapes BRCA-mediated phenotypes
Analysis of more than 17,000 tumours suggests that the contribution of germline and somatic mutations in the BRCA1 and BRCA2 genes to oncogenesis depends on tumour lineage.
- Philip Jonsson
- , Chaitanya Bandlamudi
- & Barry S. Taylor
-
Letter |
CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy
Interferon-γ induces ferroptotic cell death in tumours by suppressing cystine uptake and promoting lipid peroxidation.
- Weimin Wang
- , Michael Green
- & Weiping Zou
-
Letter |
Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring
A systematic proteomic investigation of disease mediators secreted by pancreatic stellate cells identifies leukaemia inhibitory factor (LIF) as a key factor that acts on cancer cells, promoting tumour progression and chemoresistance.
- Yu Shi
- , Weina Gao
- & Tony Hunter
-
Letter |
p38γ is essential for cell cycle progression and liver tumorigenesis
The stress-activated kinase p38γ has a role in regulating entry into the cell cycle; in the liver, it can induce cellular proliferation during regeneration and promote the development of hepatocellular carcinoma.
- Antonia Tomás-Loba
- , Elisa Manieri
- & Guadalupe Sabio
-
Article |
Prioritization of cancer therapeutic targets using CRISPR–Cas9 screens
In a screen of 324 human cancer cell lines and utilising a systematic target prioritization framework, the Werner syndrome ATP-dependent helicase is shown to be a synthetic lethal target in tumours from multiple cancer types with microsatellite instability, providing a new target for cancer drug development.
- Fiona M. Behan
- , Francesco Iorio
- & Mathew J. Garnett
-
Letter |
WRN helicase is a synthetic lethal target in microsatellite unstable cancers
Depletion of the DNA helicase WRN induced double-stranded DNA breaks, and promoted apoptosis and cell cycle arrest selectively in cancers with microsatellite instability, indicating that WRN is a promising drug target for the treatment of these cancers.
- Edmond M. Chan
- , Tsukasa Shibue
- & Adam J. Bass
-
Letter |
Efficacy of MEK inhibition in patients with histiocytic neoplasms
A proof-of-concept clinical trial of patients with histiocytoses with MAPK-pathway mutations showed durable responses to treatment with the MEK1 and MEK2 inhibitor cobimetinib, which indicates that histiocytic neoplasms are dependent on MAPK signalling.
- Eli L. Diamond
- , Benjamin H. Durham
- & David M. Hyman
-
Letter |
NR4A transcription factors limit CAR T cell function in solid tumours
Transfer of NR4A-deficient T cells expressing chimeric antigen receptors is shown to reduce tumour burden and increase survival by shifting T cell transcriptional programs away from exhaustion and towards increased effector function.
- Joyce Chen
- , Isaac F. López-Moyado
- & Anjana Rao
-
Letter |
Neutrophils escort circulating tumour cells to enable cell cycle progression
The authors show that circulating tumour cells can be found in association with neutrophils, an interaction which supports their proliferation and their ability to seed metastasis.
- Barbara Maria Szczerba
- , Francesc Castro-Giner
- & Nicola Aceto
-
Article |
De novo design of potent and selective mimics of IL-2 and IL-15
A hyper-stable de novo protein mimic of interleukin-2 computationally designed to not interact with a regulatory T-cell specific receptor subunit has improved therapeutic activity in mouse models of melanoma and colon cancer.
- Daniel-Adriano Silva
- , Shawn Yu
- & David Baker
-
Letter |
Mannose impairs tumour growth and enhances chemotherapy
Mannose reduces the growth of tumour cells by impairing the metabolism of glucose, and enhances cell death when used in combination with conventional chemotherapy.
- Pablo Sierra Gonzalez
- , James O’Prey
- & Kevin M. Ryan
-
Article |
DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells
DYNLL1 antagonizes end resection of DNA double-strand breaks, thereby inhibiting homologous repair, and the loss of DYNLL1 correlates with poor progression-free survival of patients with BRCA1-mutant ovarian cancer.
- Yizhou Joseph He
- , Khyati Meghani
- & Dipanjan Chowdhury
-
Letter |
A slow-cycling LGR5 tumour population mediates basal cell carcinoma relapse after therapy
Treatment of basal cell carcinoma with Smoothened inhibitors leaves a small population of quiescent cells that can drive relapse but can be eliminated by additional treatment with a Wnt signalling inhibitor.
- Adriana Sánchez-Danés
- , Jean-Christophe Larsimont
- & Cédric Blanpain
-
Letter |
Reprogramming human T cell function and specificity with non-viral genome targeting
A non-viral strategy to introduce large DNA sequences into T cells enables the correction of a pathogenic mutation that causes autoimmunity, and the replacement of an endogenous T-cell receptor with an engineered receptor that can recognize cancer antigens.
- Theodore L. Roth
- , Cristina Puig-Saus
- & Alexander Marson
-
Letter |
Histidine catabolism is a major determinant of methotrexate sensitivity
Histidine metabolism influences the sensitivity of cancer cells to methotrexate, with mice bearing leukaemia xenografts showing increased response to the drug upon histidine supplementation.
- Naama Kanarek
- , Heather R. Keys
- & David M. Sabatini
-
Letter |
Suppression of insulin feedback enhances the efficacy of PI3K inhibitors
Glucose–insulin feedback can reactivate PI3K in tumours treated with PI3K inhibitors, reducing therapeutic efficacy, but this effect can be reduced by using drugs or diet to suppress the insulin response.
- Benjamin D. Hopkins
- , Chantal Pauli
- & Lewis C. Cantley
-
Letter |
CRISPR screens identify genomic ribonucleotides as a source of PARP-trapping lesions
Mutations in all three genes encoding ribonuclease H2 sensitize cells to poly(ADP–ribose) polymerase inhibitors by compromising ribonucleotide excision repair.
- Michal Zimmermann
- , Olga Murina
- & Daniel Durocher
-
Letter |
Acquired resistance to IDH inhibition through trans or cis dimer-interface mutations
A new mechanism of acquired clinical resistance in two patients with acute myeloid leukaemia driven by mutant IDH2 is described, in which a second-site mutation on the wild-type allele induces therapeutic resistance to IDH2 inhibitors.
- Andrew M. Intlekofer
- , Alan H. Shih
- & Eytan M. Stein
-
Letter |
High speed of fork progression induces DNA replication stress and genomic instability
Inhibition of PARP is shown to accelerate the speed of replication fork elongation, which prevents fork stalling and induces DNA damage, with implications for genomic instability and cancer treatment.
- Apolinar Maya-Mendoza
- , Pavel Moudry
- & Jiri Bartek
-
Letter |
Codon-specific translation reprogramming promotes resistance to targeted therapy
Enzymes that catalyse modifications of wobble uridine 34 tRNA are essential for the survival of melanoma cells that rely on HIF1α-dependent metabolism through codon-dependent regulation of the translation of HIF1A mRNA.
- Francesca Rapino
- , Sylvain Delaunay
- & Pierre Close