Nature, volume 575, issue 7781, pages 217-223
The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity
Jude Canon
1
,
Karen Rex
1
,
Anne Y. Saiki
1
,
Christopher Mohr
1
,
Keegan Cooke
1
,
Dhanashri Bagal
2
,
Kevin Gaida
1
,
Tyler Holt
1
,
Charles G. Knutson
3
,
Neelima Koppada
3
,
Brian A Lanman
1
,
Jonathan Werner
1
,
Aaron S Rapaport
2
,
Tisha San Miguel
1
,
Roberto Ortiz
3, 4
,
Tao Osgood
1
,
Ji-Rong Sun
1
,
Xiaochun Zhu
3, 5
,
John D. McCarter
1
,
Laurie P. Volak
3, 6
,
Brett E Houk
7
,
Marwan G. Fakih
8
,
Bert H O'Neil
9
,
Timothy J. Price
10, 11
,
Gerald S. Falchook
12
,
Jayesh Desai
13
,
James Kuo
14
,
Ramaswamy Govindan
15
,
David S. Hong
16
,
Wenjun Ouyang
2
,
Haby Henary
7
,
Tara Arvedson
2
,
Victor J Cee
1
,
J. Russell Lipford
1
1
Amgen Research, Amgen Inc, Thousand Oaks, USA
|
2
Amgen Research, Amgen Inc, South San Francisco, USA
|
3
Amgen Research, Amgen Inc, Cambridge, USA
|
4
Pfizer, La Jolla, USA
|
5
Takeda, Cambridge, USA
|
6
Celgene, San Diego, USA
|
7
Amgen Clinical Development, Amgen Inc, Thousand Oaks, USA
|
8
City of Hope, Duarte, USA
|
9
Indiana university school of medicine, Indianapolis, USA
|
12
Sarah Cannon Research Institute, Denver, USA
|
14
Scientia Clinical Research, Randwick, New South Wales, Australia
|
Publication type: Journal Article
Publication date: 2019-10-30
Multidisciplinary
Abstract
KRAS is the most frequently mutated oncogene in cancer and encodes a key signalling protein in tumours1,2. The KRAS(G12C) mutant has a cysteine residue that has been exploited to design covalent inhibitors that have promising preclinical activity3–5. 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 KRASG12C 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 KRASG12D 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. 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.
Top-30
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npj Precision Oncology
7 publications, 0.48%
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Citations by publishers
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Elsevier
291 publications, 20.12%
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Springer Nature
246 publications, 17.01%
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81 publications, 5.6%
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Frontiers Media S.A.
65 publications, 4.5%
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American Association for Cancer Research (AACR)
64 publications, 4.43%
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Taylor & Francis
38 publications, 2.63%
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Royal Society of Chemistry (RSC)
22 publications, 1.52%
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American Society of Clinical Oncology (ASCO)
21 publications, 1.45%
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SAGE
18 publications, 1.24%
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American Association for the Advancement of Science (AAAS)
14 publications, 0.97%
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Proceedings of the National Academy of Sciences (PNAS)
13 publications, 0.9%
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12 publications, 0.83%
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12 publications, 0.83%
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BMJ
12 publications, 0.83%
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11 publications, 0.76%
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Bentham Science
9 publications, 0.62%
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eLife Sciences Publications
9 publications, 0.62%
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Oxford University Press
9 publications, 0.62%
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Portland Press
8 publications, 0.55%
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6 publications, 0.41%
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4 publications, 0.28%
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50
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- We do not take into account publications without a DOI.
- Statistics recalculated only for publications connected to researchers, organizations and labs registered on the platform.
- Statistics recalculated weekly.
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Canon J. et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity // Nature. 2019. Vol. 575. No. 7781. pp. 217-223.
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Canon J., Rex K., Saiki A. Y., Mohr C., Cooke K., Bagal D., Gaida K., Holt T., Knutson C. G., Koppada N., Lanman B. A., Werner J., Rapaport A. S., San Miguel T., Ortiz R., Osgood T., Sun J., Zhu X., McCarter J. D., Volak L. P., Houk B. E., Fakih M. G., O'Neil B. H., Price T. J., Falchook G. S., Desai J., Kuo J., Govindan R., Hong D. S., Ouyang W., Henary H., Arvedson T., Cee V. J., Lipford J. R. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity // Nature. 2019. Vol. 575. No. 7781. pp. 217-223.
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TY - JOUR
DO - 10.1038/s41586-019-1694-1
UR - https://doi.org/10.1038/s41586-019-1694-1
TI - The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity
T2 - Nature
AU - Canon, Jude
AU - Rex, Karen
AU - Saiki, Anne Y.
AU - Mohr, Christopher
AU - Cooke, Keegan
AU - Bagal, Dhanashri
AU - Gaida, Kevin
AU - Holt, Tyler
AU - Knutson, Charles G.
AU - Koppada, Neelima
AU - Lanman, Brian A
AU - Werner, Jonathan
AU - Rapaport, Aaron S
AU - San Miguel, Tisha
AU - Ortiz, Roberto
AU - Osgood, Tao
AU - Sun, Ji-Rong
AU - Zhu, Xiaochun
AU - McCarter, John D.
AU - Volak, Laurie P.
AU - Houk, Brett E
AU - Fakih, Marwan G.
AU - O'Neil, Bert H
AU - Price, Timothy J.
AU - Falchook, Gerald S.
AU - Desai, Jayesh
AU - Kuo, James
AU - Govindan, Ramaswamy
AU - Hong, David S.
AU - Ouyang, Wenjun
AU - Henary, Haby
AU - Arvedson, Tara
AU - Cee, Victor J
AU - Lipford, J. Russell
PY - 2019
DA - 2019/10/30 00:00:00
PB - Springer Nature
SP - 217-223
IS - 7781
VL - 575
SN - 0028-0836
SN - 1476-4687
ER -
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@article{2019_Canon,
author = {Jude Canon and Karen Rex and Anne Y. Saiki and Christopher Mohr and Keegan Cooke and Dhanashri Bagal and Kevin Gaida and Tyler Holt and Charles G. Knutson and Neelima Koppada and Brian A Lanman and Jonathan Werner and Aaron S Rapaport and Tisha San Miguel and Roberto Ortiz and Tao Osgood and Ji-Rong Sun and Xiaochun Zhu and John D. McCarter and Laurie P. Volak and Brett E Houk and Marwan G. Fakih and Bert H O'Neil and Timothy J. Price and Gerald S. Falchook and Jayesh Desai and James Kuo and Ramaswamy Govindan and David S. Hong and Wenjun Ouyang and Haby Henary and Tara Arvedson and Victor J Cee and J. Russell Lipford},
title = {The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity},
journal = {Nature},
year = {2019},
volume = {575},
publisher = {Springer Nature},
month = {oct},
url = {https://doi.org/10.1038/s41586-019-1694-1},
number = {7781},
pages = {217--223},
doi = {10.1038/s41586-019-1694-1}
}
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Canon, Jude, et al. “The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity.” Nature, vol. 575, no. 7781, Oct. 2019, pp. 217-223. https://doi.org/10.1038/s41586-019-1694-1.