The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity
Jude 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 Show all
Nature | NATURE PUBLISHING GROUP | Published : 2019
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..View full abstract
Awarded by Office of Science, Office of Basic Energy Sciences, of the US Department of Energy
Awarded by NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
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.