 The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunityJude Canon (),
Karen Rex,
Anne Y. Saiki,
Christopher Mohr,
Keegan Cooke,
Dhanashri Bagal,
Kevin Gaida,
Tyler Holt,
Charles G. Knutson,
Neelima Koppada,
Brian A. Lanman,
Jonathan Werner,
Aaron S. Rapaport,
Tisha San Miguel,
Roberto Ortiz,
Tao Osgood,
Ji-Rong Sun,
Xiaochun Zhu,
John D. McCarter,
Laurie P. Volak,
Brett E. Houk,
Marwan G. Fakih,
Bert H. O’Neil,
Timothy J. Price,
Gerald S. Falchook,
Jayesh Desai,
James Kuo,
Ramaswamy Govindan,
David S. Hong,
Wenjun Ouyang,
Haby Henary,
Tara Arvedson,
Victor J. Cee and
J. Russell Lipford ()
Nature, 2019, vol. 575, issue 7781, 217-223 Abstract: 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. Date: 2019 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:575:y:2019:i:7781:d:10.1038_s41586-019-1694-1 Ordering information: This journal article can be ordered from DOI: 10.1038/s41586-019-1694-1 Access Statistics for this article Nature is currently edited by Magdalena Skipper More articles in Nature from Nature |
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