Targeted therapies articles within Nature

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  • Article
    | Open Access

    RMC-7977, a compound that exhibits potent inhibition of the active states of mutant and wild-type KRAS, NRAS and HRAS variants has a strong anti-tumour effect on RAS-addicted tumours and is well tolerated in preclinical models.

    • Matthew Holderfield
    • , Bianca J. Lee
    •  & Mallika Singh

  • Article
    | Open Access

    Poly(ADP-ribose) polymerase 1 (PARP1) functions together with TIMELESS and TIPIN to protect the replisome in early S phase from transcription–replication conflicts, and inhibiting PARP1 enzymatic activity may suffice for treatment efficacy in homologous recombination-deficient settings.

    • Michalis Petropoulos
    • , Angeliki Karamichali
    •  & Thanos D. Halazonetis

  • Article |

    Induction of APOBEC3A in response to targeted therapies drives evolution of drug-tolerant persister cells, suggesting that its suppression may represent a potential therapeutic strategy in the prevention of acquired resistance to lung cancer targeted therapy.

    • Hideko Isozaki
    • , Ramin Sakhtemani
    •  & Aaron N. Hata

  • Article
    | Open Access

    A non-covalent inhibitor that binds preferentially to the inactive state of KRAS while sparing NRAS and HRAS is reported, indicating that most KRAS oncoproteins cycle between an active state and an inactive state in cancer cells.

    • Dongsung Kim
    • , Lorenz Herdeis
    •  & Piro Lito

  • Article
    | Open Access

    Revumenib, a potent and selective oral inhibitor of the menin–KMT2A interaction, is associated with a low frequency of treatment-related adverse events and promising clinical activity in patients with relapsed or refractory acute leukaemia.

    • Ghayas C. Issa
    • , Ibrahim Aldoss
    •  & Eytan M. Stein

  • Article |

    A translationally silent KRASG60G mutation, preventing the formation of a cryptic splice donor site and  enabling expression of KRAS(Q61K), reveals a vulnerability in RASQ61 cancers that are therapeutically exploitable in a mutant-selective manner.

    • Yoshihisa Kobayashi
    • , Chhayheng Chhoeu
    •  & Pasi A. Jänne

  • Article
    | Open Access

    A survey of potency and efficacy of 2,025 clinically relevant two-drug combinations against 125 molecularly characterized breast, colorectal and pancreatic cancer cell lines identifies rare synergistic effects of anticancer drugs, informing rational combination treatments for specific cancer subtypes.

    • Patricia Jaaks
    • , Elizabeth A. Coker
    •  & Mathew J. Garnett

  • Article
    | Open Access

    PROTAC degrader–induced SWI/SNF inactivation abolishes DNA accessibility at enhancer elements of oncogenes and also tempers supra-physiologic expression of driver transcription factors, resulting in potent inhibition of tumour growth in mouse models.

    • Lanbo Xiao
    • , Abhijit Parolia
    •  & Arul M. Chinnaiyan

  • Article
    | Open Access

    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 |

    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 |

    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 |

    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 |

    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

  • Letter |

    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 |

    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 |

    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 |

    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 |

    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

  • 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

  • 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 |

    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

  • 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

  • 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 |

    In studies in mammalian cells, polymerase theta (Polθ, also known as POLQ) is identified as the polymerase responsible for non-homologous end joining DNA repair; this DNA repair pathway acts in many tumours when homologous recombination is inactivated and the identification of the polymerase responsible may aid the development of new therapeutic approaches.

    • Raphael Ceccaldi
    • , Jessica C. Liu
    •  & Alan D. D’Andrea

  • Letter |

    A novel anti-microRNA delivery platform that targets the acidic tumour microenvironment, in which a chosen anti-miRNA is coupled to a peptide that can transport the anti-miRNA across cell membranes specifically in an acidic environment.

    • Christopher J. Cheng
    • , Raman Bahal
    •  & Frank J. Slack

  • Letter |

    Using a structure-based approach, small molecule inhibitors that selectively target the GTPase Ral are identified and characterized; these first-generation inhibitors will be valuable tools for elucidating the Ral signalling pathway and constitute a step towards developing Ral-specific agents for cancer therapy.

    • Chao Yan
    • , Degang Liu
    •  & Dan Theodorescu

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