Cancer therapy articles within Nature

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  • Article |

    In a basket trial design, the efficacy of the pan-HER kinase inhibitor neratinib is tested in patients with 21 different tumour types, and responses are determined by mutation and tissue type, and are restricted to HER2-mutant cancers.

    • David M. Hyman
    • , Sarina A. Piha-Paul
    •  & David B. Solit

  • Article |

    A high-resolution structure of the human ribosome determined by cryo-electron microscopy visualizes numerous RNA modifications that are concentrated at functional sites with an extended shell, and suggests the possibility of designing more specific ribosome-targeting drugs.

    • S. Kundhavai Natchiar
    • , Alexander G. Myasnikov
    •  & Bruno P. Klaholz

  • Letter |

    An immune fitness model for tumours under checkpoint blockade immunotherapy is proposed, through which the authors show that the presentation and recognition properties of dominant neoantigens distributed over tumour subclones are predictive of response in melanoma and lung cancer cohorts.

    • Marta Łuksza
    • , Nadeem Riaz
    •  & Benjamin D. Greenbaum

  • Letter |

    The identification of an ERK2–JUNB–FRA1 signalling pathway that drives addiction to therapeutic drugs in cancer cells, and an ERK2-dependent phenotype switch that precedes cell death after drug withdrawal, may help to guide therapies that exploit the addiction phenotype.

    • Xiangjun Kong
    • , Thomas Kuilman
    •  & Daniel S. Peeper

  • Letter |

    BRAF-inhibition resistance in metastatic melanoma occurs through p21-activated kinase-mediated reactivation of ERK, whereas resistance to combined BRAF and MEK inhibition occurs through p21-activated kinase-mediated regulation of JNK and β-catenin phosphorylation, mTOR pathway activation and apoptosis inhibition in many patients.

    • Hezhe Lu
    • , Shujing Liu
    •  & Wei Guo

  • Letter |

    Mouse models of breast carcinoma and other solid tumours show that selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors not only induce tumour cell cycle arrest but also promote anti-tumour immunity.

    • Shom Goel
    • , Molly J. DeCristo
    •  & Jean J. Zhao

  • Letter |

    The cysteine protease CPR-4, a cathepsin B homologue, is identified as a radiation-induced bystander effect (RIBE) factor in nematodes in response to ultraviolet or ionizing radiation, and causes inhibition of cell death and increased embryonic lethality.

    • Yu Peng
    • , Man Zhang
    •  & Ding Xue

  • Letter |

    Through drug exposure, a rare, transient transcriptional program characterized by high levels of expression of known resistance drivers can get ‘burned in’, leading to the selection of cells endowed with a transcriptional drug resistance and thus more chemoresistant cancers.

    • Sydney M. Shaffer
    • , Margaret C. Dunagin
    •  & Arjun Raj

  • Article |

    LGR5+ cells in human colorectal cancer tissue xenografted into mice act as cancer stem cells, and differentiated cancer cells can revert to cancer stem cells and express LGR5 after ablation of existing LGR5+ cells.

    • Mariko Shimokawa
    • , Yuki Ohta
    •  & Toshiro Sato

  • Letter |

    The selective allosteric ABL1 inhibitor ABL001 (asciminib) represents a new inhibitory mechanism for BCR–ABL1-driven malignancies, and its efficacy and evolving mechanisms of resistance do not overlap with those of other BCR–ABL1 kinase inhibitors.

    • Andrew A. Wylie
    • , Joseph Schoepfer
    •  & William R. Sellers

  • Letter |

    Introducing chimeric antigen receptors into the endogenous T-cell receptor locus reduces tonic signalling, averts accelerated T-cell differentiation and delays T-cell exhaustion, leading to enhanced function and anti-tumour efficacy compared to random integrations.

    • Justin Eyquem
    • , Jorge Mansilla-Soto
    •  & Michel Sadelain

  • Letter |

    PI3Kδ controls the expression of the recombinogenic enzyme AID; excessive AID activity caused by PI3Kδ inhibition can induce genomic instability in leukaemia and lymphoma cells, as well as in patients with chronic lymphocytic leukaemia treated with PI3Kδ inhibitors.

    • Mara Compagno
    • , Qi Wang
    •  & Roberto Chiarle

  • Brief Communications Arising |

    • Zhaleh Safikhani
    • , Nehme El-Hachem
    •  & Benjamin Haibe-Kains

  • Brief Communications Arising |

    • Zhaleh Safikhani
    • , Nehme El-Hachem
    •  & Benjamin Haibe-Kains

  • Letter |

    SHP099, a selective inhibitor of signalling meditator SHP2 with drug-like properties, has an allosteric mechanism of action whereby it stabilizes SHP2 in an auto-inhibited conformation, and suppresses RAS–ERK signalling and proliferation in receptor-tyrosine-kinase-driven cancer cell lines and mouse tumour xenograft models.

    • Ying-Nan P. Chen
    • , Matthew J. LaMarche
    •  & Pascal D. Fortin

  • Article |

    A systematic screen identifies FGFR1 signalling reactivation as an adaptive resistance mechanism after MEK inhibition specific for KRAS tumours, which can be targeted by combined inhibition with the clinically approved drugs trametinib and ponatinib.

    • Eusebio Manchado
    • , Susann Weissmueller
    •  & Scott W. Lowe

  • Letter |

    The development of a nanoparticle RNA vaccine is reported that preferentially targets dendritic cells after systemic administration, and is shown to provide durable interferon-α-dependent antigen-specific immunity in mouse tumour models; initial results in advanced melanoma patients indicate potential efficacy in humans.

    • Lena M. Kranz
    • , Mustafa Diken
    •  & Ugur Sahin

  • Letter |

    Inhibitors of the mTOR kinase are in clinical trials for the treatment of cancer; here, mutations in mTOR that can lead to drug resistance are investigated and the results are used to design a new class of mTOR inhibitors that can overcome this resistance.

    • Vanessa S. Rodrik-Outmezguine
    • , Masanori Okaniwa
    •  & Kevan M. Shokat

  • Letter |

    A known oncogene, MITF, resides in a region of chromosome 3 that is amplified in melanomas and associated with poor prognosis; now, a long non-coding RNA gene, SAMMSON, is shown to also lie in this region, to also act as a melanoma-specific survival oncogene, and to be a promising therapeutic target for anti-melanoma therapy.

    • Eleonora Leucci
    • , Roberto Vendramin
    •  & Jean-Christophe Marine

  • Article |

    An epithelial-to-mesenchymal transition (EMT) lineage-tracing system in a mouse model of breast-to-lung metastasis reveals that although some cells undergo EMT in a primary epithelial tumour, the lung metastases mainly arise from cells that have not undergone EMT; in addition, cells that have undergone EMT appear more resistant to chemotherapy.

    • Kari R. Fischer
    • , Anna Durrans
    •  & Dingcheng Gao

  • Letter |

    Expression of the tumour suppressor PTEN in disseminated primary tumour cells is lost after tumour cells metastasize to the brain, with downregulation instigated by microRNAs from astrocytes, which are transferred from cell to cell by exosomes; these findings reveal the dynamic nature of metastatic cancer cells when adapting to a new tissue environment.

    • Lin Zhang
    • , Siyuan Zhang
    •  & Dihua Yu

  • Letter |

    Next-generation RAF inhibitors that inhibit oncogenic BRAF without inducing paradoxical pathway activation in cells with mutant RAS might yield improved safety and more durable efficacy.

    • Chao Zhang
    • , Wayne Spevak
    •  & Gideon Bollag

  • Letter |

    BET inhibitors that target bromodomain chromatin readers such as BRD4 are being explored as potential therapeutics in cancer; here, in a MLL–AF9 mouse leukaemia model, resistance to BET inhibitors is shown to emerge from leukaemia stem cells, and be partly due to increased Wnt/β-catenin signalling.

    • Chun Yew Fong
    • , Omer Gilan
    •  & Mark A. Dawson

  • Letter |

    BET bromodomain inhibitors are being explored as potential therapeutics in cancer; here, AML cells are shown to evade sensitivity to BET inhibition through rewiring the transcriptional regulation of BRD4 target genes such as MYC in a process that is facilitated by suppression of PRC2 and WNT signalling activation.

    • Philipp Rathert
    • , Mareike Roth
    •  & Johannes Zuber

  • Article |

    This study describes the long-awaited crystal structures for hypoxia-inducible factor (HIF) heterodimers, including complexes bound to small molecules and DNA; the HIF–ARNT architecture is distinct from the bHLH-PAS-containing CLOCK–BMAL1 heterodimer, and HIF mutations linked to cancer can be mapped to important structural regions, with the structures providing future reference for small-molecule drug discovery efforts.

    • Dalei Wu
    • , Nalini Potluri
    •  & Fraydoon Rastinejad

  • Letter |

    The authors show that a large fraction of tumour mutations is immunogenic and predominantly recognized by CD4+ T cells; they use these data to design synthetic messenger-RNA-based vaccines specific against tumour mutations, and show that these can reject tumours in mice.

    • Sebastian Kreiter
    • , Mathias Vormehr
    •  & Ugur Sahin

  • Letter |

    Tumour cells respond to an effective, targeted drug treatment with BRAF, ALK or EGFR kinase inhibitors by inducing a complex network of secreted signals that promote tumour growth, dissemination and metastasis of drug-resistant cancer cell clones, and increase the survival of drug-sensitive tumour cells, potentially contributing to incomplete tumour regression.

    • Anna C. Obenauf
    • , Yilong Zou
    •  & Joan Massagué

  • Letter |

    Loss of REV7 is shown to regulate end resection of double-stranded DNA breaks in BRCA1-deficient cells, leading to PARP inhibitor resistance and restoration of homologous recombination; REV7 dictates pathway choice in BRCA1-deficient cells and during immunoglobulin class switching.

    • Guotai Xu
    • , J. Ross Chapman
    •  & Sven Rottenberg

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