Nature (London), 2019-11, Vol.575 (7781), p.217-223
- Canon, Jude
- Rex, Karen
- Saiki, Anne Y
- Mohr, Christopher
- Cooke, Keegan
- Bagal, Dhanashri
- Gaida, Kevin
- Holt, Tyler
- Knutson, Charles G
- Koppada, Neelima
- Lanman, Brian A
- Werner, Jonathan
- Rapaport, Aaron S
- San Miguel, Tisha
- Ortiz, Roberto
- Osgood, Tao
- Sun, Ji-Rong
- Zhu, Xiaochun
- McCarter, John D
- Volak, Laurie P
- Houk, Brett E
- Fakih, Marwan G
- O'Neil, Bert H
- Price, Timothy J
- Falchook, Gerald S
- Desai, Jayesh
- Kuo, James
- Govindan, Ramaswamy
- Hong, David S
- Ouyang, Wenjun
- Henary, Haby
- Arvedson, Tara
- Cee, Victor J
- Lipford, J Russell
2019
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- Autor(en) / Beteiligte
- Canon, Jude
- Rex, Karen
- Saiki, Anne Y
- Mohr, Christopher
- Cooke, Keegan
- Bagal, Dhanashri
- Gaida, Kevin
- Holt, Tyler
- Knutson, Charles G
- Koppada, Neelima
- Lanman, Brian A
- Werner, Jonathan
- Rapaport, Aaron S
- San Miguel, Tisha
- Ortiz, Roberto
- Osgood, Tao
- Sun, Ji-Rong
- Zhu, Xiaochun
- McCarter, John D
- Volak, Laurie P
- Houk, Brett E
- Fakih, Marwan G
- O'Neil, Bert H
- Price, Timothy J
- Falchook, Gerald S
- Desai, Jayesh
- Kuo, James
- Govindan, Ramaswamy
- Hong, David S
- Ouyang, Wenjun
- Henary, Haby
- Arvedson, Tara
- Cee, Victor J
- Lipford, J Russell
- Titel
- The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity
- Ist Teil von
- Nature (London), 2019-11, Vol.575 (7781), p.217-223
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2019
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- KRAS is the most frequently mutated oncogene in cancer and encodes a key signalling protein in tumours . The KRAS(G12C) mutant has a cysteine residue that has been exploited to design covalent inhibitors that have promising preclinical activity . Here we optimized a series of inhibitors, using novel binding interactions to markedly enhance their potency and selectivity. Our efforts have led to the discovery of AMG 510, which is, to our knowledge, the first KRAS(G12C) inhibitor in clinical development. In preclinical analyses, treatment with AMG 510 led to the regression of KRAS tumours and improved the anti-tumour efficacy of chemotherapy and targeted agents. In immune-competent mice, treatment with AMG 510 resulted in a pro-inflammatory tumour microenvironment and produced durable cures alone as well as in combination with immune-checkpoint inhibitors. Cured mice rejected the growth of isogenic KRAS tumours, which suggests adaptive immunity against shared antigens. Furthermore, in clinical trials, AMG 510 demonstrated anti-tumour activity in the first dosing cohorts and represents a potentially transformative therapy for patients for whom effective treatments are lacking.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0028-0836eISSN: 1476-4687DOI: 10.1038/s41586-019-1694-1Titel-ID: cdi_proquest_journals_2315039822
- Format
- –
- Schlagworte
- Adaptive immunity, Analysis, Animals, Anticancer properties, Antigens, Antineoplastic Agents - administration & dosage, Antineoplastic Agents - chemistry, Antineoplastic Agents - pharmacology, Antineoplastic Agents - therapeutic use, Cancer therapies, Cell Proliferation - drug effects, Chemotherapy, Clinical trials, Colorectal cancer, Crystal structure, Cures, Drug Synergism, Humans, Immune checkpoint inhibitors, Immunity, Immunotherapy, Inflammation, Inflammation - chemically induced, Inflammation - immunology, Inflammation - pathology, Inhibitors, K-Ras protein, Ligands, Lung cancer, Lung Neoplasms - drug therapy, Lung Neoplasms - genetics, Lung Neoplasms - immunology, Lung Neoplasms - pathology, Lymphocytes, Mass spectrometry, Mice, Mutation, Phosphorylation - drug effects, Piperazines - administration & dosage, Piperazines - chemistry, Piperazines - pharmacology, Piperazines - therapeutic use, Proteins, Proto-Oncogene Proteins p21(ras) - antagonists & inhibitors, Proto-Oncogene Proteins p21(ras) - genetics, Pyridines - administration & dosage, Pyridines - chemistry, Pyridines - pharmacology, Pyridines - therapeutic use, Pyrimidines - administration & dosage, Pyrimidines - chemistry, Pyrimidines - pharmacology, Pyrimidines - therapeutic use, Ras genes, Regression analysis, Scientific imaging, Selectivity, Signal transduction, Signal Transduction - drug effects, Treatment Outcome, Tumor microenvironment, Tumor Microenvironment - drug effects, Tumor Microenvironment - immunology, Tumor necrosis factor inhibitors, Tumors