Cancer therapeutic resistance articles within Nature

Featured

  • 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

    We uncover key processes of the genomic evolution of small cell lung cancer under therapy, identify the common ancestor as the source of clonal diversity at relapse and show central genomic patterns associated with drug response.

    • Julie George
    • , Lukas Maas
    •  & Roman K. Thomas

  • 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

    RHOJ regulates epithelial-to-mesenchymal-transition-associated resistance to chemotherapy by enhancing the response to replicative stress and activating the DNA damage response, enabling tumour cells to rapidly repair DNA lesions induced by chemotherapy.

    • Maud Debaugnies
    • , Sara Rodríguez-Acebes
    •  & Cédric Blanpain

  • Article |

    Somatic mutations in MEN1 are identified in patients with leukaemia treated with a novel chromatin-targeting therapy, and the mechanism by which these mutations mediate therapeutic resistance is characterized.

    • Florian Perner
    • , Eytan M. Stein
    •  & Sheng F. Cai

  • Article
    | Open Access

    Indole-3-acetic acid (3-IAA), a tryptophan metabolite derived from the gut microbiota, is associated with a better response to chemotherapy in pancreatic ductal adenocarcinoma (PDAC), and dietary interventions could have a role in the treatment of PDAC.

    • Joseph Tintelnot
    • , Yang Xu
    •  & Nicola Gagliani

  • Article |

    Deep whole-genome sequencing of serial blood samples and matched metastatic tissue reveals that circulating tumour DNA profiling enables detailed study of treatment-driven subclone dynamics, epigenomics and genome-wide somatic evolution in metastatic human cancers.

    • Cameron Herberts
    • , Matti Annala
    •  & Alexander W. Wyatt

  • Article |

    A genetic lineage-tracing system in human colorectal organoids identifies a population of dormant cancer cells that persists during chemotherapy and enables cancer regrowth, and the cell-adhesion molecule COL17A1 has a key role in the process of breaking dormancy.

    • Yuki Ohta
    • , Masayuki Fujii
    •  & Toshiro Sato

  • Article |

    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 |

    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 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 |

    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 |

    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 |

    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

  • 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 |

    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

  • 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

  • Article |

    Mutations that dysregulate Notch1 and Ras/PI3K signalling are common in T-cell acute lymphoblastic leukaemia; here, treatment with a PI3K inhibitor is shown to induce drug resistance that is associated with downregulation of activated Notch1 signalling, suggesting that inhibition of both Notch1 and PI3K could promote drug resistance.

    • Monique Dail
    • , Jason Wong
    •  & Kevin Shannon

  • Outlook |

    Even as cancer therapies improve, basic questions about drug resistance, tumour spread and the role of normal tissue remain unanswered.

    • Katherine Bourzac

  • Letter |

    A new mechanism by which acute myeloid leukaemia patients become resistant to Ara-C and a newer treatment, ribavirin, is uncovered; these drugs can be glucuronidated and thereby inactivated by members of the UDP glucuronosyltransferase family of enzymes activated through GLI1 signalling.

    • Hiba Ahmad Zahreddine
    • , Biljana Culjkovic-Kraljacic
    •  & Katherine L. B. Borden

  • Letter |

    Expression of more than 15,500 genes individually in a melanoma cell line treated with RAF, MEK, ERK or combined RAF–MEK inhibitors reveals a cyclic-AMP-dependent melanocytic signalling network associated with drug resistance; this may represent a novel therapeutic target for melanoma treatment.

    • Cory M. Johannessen
    • , Laura A. Johnson
    •  & Levi A. Garraway

  • Outlook |

    Complex mathematical models are helping researchers understand cancer's evolution and providing clues on how to thwart drug resistance.

    • Katharine Gammon

  • News & Views |

    Tumour cells can respond to targeted immune-cell therapies by losing proteins that mark them as being cancerous. Subverting this resistance mechanism may lead to more durable cancer-treatment strategies. See Letter p.412

    • Antoni Ribas
    •  & Paul C. Tumeh

  • Letter |

    A genetically engineered mouse model is used to determine the mechanism of acquired resistance to adoptive therapy with cytotoxic T cells specific for a melanocytic differentiation antigen; tumour necrosis factor (TNF)-α is identified as a crucial factor that causes reversible dedifferentiation of mouse and human melanoma cells.

    • Jennifer Landsberg
    • , Judith Kohlmeyer
    •  & Thomas Tüting

  • Letter |

    Biochemical and structural analysis of the drug transporter P-glycoprotein in Caenorhabditis elegans at a resolution of 3.4 angstroms is used to generate a homology model of the human protein and supports a picture in which P-glycoprotein uses the energy from ATP hydrolysis to expel lipophilic molecules from the inner leaflet of the cell membrane.

    • Mi Sun Jin
    • , Michael L. Oldham
    •  & Jue Chen

  • News & Views |

    Rare tumour cells with mutations that confer drug resistance can go undetected by standard testing procedures, according to two studies, which show that such mutations can be detected in patients' blood. See Letters p.532 and p.537

    • Eduardo Vilar
    •  & Josep Tabernero

  • Letter |

    This work on colorectal cancer shows that secondary mutations in KRAS that confer resistance to panitumumab, an anti-EGFR monoclonal antibody, are already present when antibody treatment begins; the apparent inevitability of resistance suggests that combinations of drugs targeting at least two different oncogenic pathway will be needed for treatment.

    • Luis A. Diaz Jr
    • , Richard T. Williams
    •  & Bert Vogelstein

  • News & Views |

    A drug for treating melanoma is ineffective in colorectal cancers that have the same causative mutation. Studies of how cells adapt to the drug reveal why this is so, and suggest combination therapies that may be more effective. See Letter p.100

    • David B. Solit
    •  & Pasi A. Jänne

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