@article{b9b59cce4412494bad3f5a012b12df1d,
title = "The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity",
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.",
author = "Jude Canon and Karen Rex and Saiki, {Anne Y.} and Christopher Mohr and Keegan Cooke and Dhanashri Bagal and Kevin Gaida and Tyler Holt and Knutson, {Charles G.} and Neelima Koppada and Lanman, {Brian A.} and Jonathan Werner and Rapaport, {Aaron S.} and {San Miguel}, Tisha and Roberto Ortiz and Tao Osgood and Sun, {Ji Rong} and Xiaochun Zhu and McCarter, {John D.} and Volak, {Laurie P.} and Houk, {Brett E.} and Fakih, {Marwan G.} and O{\textquoteright}Neil, {Bert H.} and Price, {Timothy J.} and Falchook, {Gerald S.} and Jayesh Desai and James Kuo and Ramaswamy Govindan and Hong, {David S.} and Wenjun Ouyang and Haby Henary and Tara Arvedson and Cee, {Victor J.} and Lipford, {J. Russell}",
note = "Funding Information: Competing interests J.C., K.R., A.Y.S., C.M., K.C., D.B., K.G., T.H., C.G.K., N.K., B.A.L., J.W., A.S.R., R.S.M., R.O., T.O., J.-R.S., X.Z., J.D.M., L.P.V., B.E.H., W.O., H.H., T.A., V.J.C. and J.R.L. were employees and stock holders of Amgen at the time of data collection. M.G.F. has received grant and research support from AstraZeneca, Amgen and Novartis; served as a consultant for Array BioPharma, Amgen and Seattle Genetics; and has been part of the speakers bureau for Amgen. B.H.O. has received honoraria from Amgen. T.J.P. has received grants and research support from Amgen. G.S.F. is employed by HealthONE and the Sarah Cannon Research Institute; has served in a consulting or advisory capacity for EMD Serono and Fujifilm; has received research funding from 3-V Biosciences, Abbvie, ADC Therapeutics, Aileron, American Society of Clinical Oncology, Amgen, ARMO, AstraZeneca, BeiGene, Bioatla, Biothera, Celldex, Celgene, Ciclomed, Curegenix, Curis, DelMar, eFFECTOR, Eli Lilly, EMD Serono, Exelixis, Fujifilm, Genmab, GlaxoSmithKline, Hutchison MediPharma, Ignyta, Incyte, Jacobio, Jounce, Kolltan, Loxo, MedImmune, Millennium, Merck, Mirna Therapeutics, the National Institutes of Health, Novartis, OncoMed, Oncothyreon, Precision Oncology, Regeneron, Rgenix, Ribon, Strategia, Syndax, Taiho, Takeda, Tarveda, Tesaro, Tocagen, Turning Point Therapeutics, the UT MD Anderson Cancer Center and Vegenics; receives royalties from Wolters Kluwer; and has also received travel, accommodation and related expenses from Bristol-Myers Squibb, EMD Serono, Fujifilm, Millennium and the Sarah Cannon Research Institute. J.D. has served in a consulting or advisory capacity for Amgen, BeiGene, Bionomics, Eisai, Eli Lilly and Novartis; and received research funding from Bionomics, GlaxoSmithKline, Novartis and Roche. J.K. has received travel, accommodation and expenses from Bristol-Myers Squibb, MSD and Zucero Therapeutics. R.G. has served in a consulting or advisory capacity for AbbVie, Adaptimmune, AstraZeneca, Celgene, Ignyta, Inivata, Merck, Nektar, Pfizer and Roche. D.S.H. has stock and other ownership interests in Molecular Match, OncoResponse and Presagia; has served in a consulting or advisory capacity for Alpha Insights, Axiom, Adaptimmune, Baxter, Bayer, Genentech, GLG, Group H, Guidepoint Global, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Seattle Genetics, Takeda and Trieza Therapeutics; has received research and/or grant funding from AbbVie, Adaptimmune, Amgen, AstraZeneca, Bayer, BMS, Daiichi-Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Eli Lilly, LOXO, Merck, MedImmune, Mirati, Mirna Therapeutics, Molecular Templates, Mologen, NCI-CTEP, Novartis, Pfizer, Seattle Genetics and Takeda; and has received travel, accommodation and expenses from Genmab, Loxo Oncology, ASCO, AACR, SITC and Mirna Therapeutics. Funding Information: Acknowledgements We thank N. Moua Vang, P. Achanta, J. Estrada, P. Mitchell, T. Tsuruda, D. Mohl, C. Liu, J. Lofgren, R. Shimanovich, P. Agarwal, R. S. Foti, Y. B. Yu, J. Yadav, M. Singh, J. Nam, C. Wang, R. Pham, W. Rufai, T. McElroy, S. Tiso, M. Farley, J. Ngang, D. Wu, R. Dawson, J. Reidy, J. Egen, R. Kendall, P. J. Beltran, M. Eschenberg, S. Caenepeel, P. Hughes, A. Coxon, F. Martin, P. K. Morrow, S. Agrawal, D. Nagorsen and G. Friberg for their support and contributions; all of the patients who participated in the AMG 510 first-in-human clinical trial; and the staff of Crystallographic Consulting and the Advanced Light Source at beamline 5.0.1 for their data collection support. The Berkeley Center for Structural Biology is supported in part by the National Institutes of Health, National Institute of General Medical Sciences and the Howard Hughes Medical Institute. The Advanced Light Source is supported by the Director, Office of Science, Office of Basic Energy Sciences, of the US Department of Energy under contract no. DE-AC02-05CH11231. Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2019",
month = nov,
day = "7",
doi = "10.1038/s41586-019-1694-1",
language = "English (US)",
volume = "575",
pages = "217--223",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7781",
}