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 activity3,4,5. 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.
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Data availability
Most of the data generated or analysed during this study are included in this published Article or available as Source Data. X-ray crystallographic coordinates and structure factor files have been deposited in the Protein Data Bank (PDB: 6OIM). Other data that support the findings of this study are available from the corresponding authors. Qualified researchers may request data from Amgen clinical studies. Further details are available at http://www.amgen.com/datasharing.
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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.
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Authors and Affiliations
Contributions
B.A.L. oversaw the design and synthesis of compounds. C.M. solved the crystal structure of AMG 510. J.D.M. and T.A. designed the nucleotide-exchange assay and mass spectrometry experiment with recombinant KRAS, and T.S.M. and A.Y.S. developed the assays. L.P.V. and C.G.K. oversaw the bioanalytical assessment of AMG 510. J.-R.S., T.H., K.C., K.R., A.Y.S. and T.O. executed and analysed in vivo studies. L.P.V., X.Z. and R.O. developed methods, and N.K. quantified KRAS(G12C)–AMG 510 covalent adducts in cells and tumour samples. L.P.V., R.O. and X.Z. developed and executed the SILAC study to determine the half-life of KRAS(G12C). J.R.L., A.Y.S., T.A., W.O. and V.J.C. designed, and A.Y.S., T.S.M., A.S.R. and K.G. executed in vitro experiments. J.W. generated the immunohistochemical data. D.B. designed and analysed proteomic experiments. B.E.H. provided clinical pharmacokinetic data. J.C., K.R. and K.C. designed the in vivo experiments. H.H. oversaw the clinical development. M.G.F., B.H.O., T.J.P., G.S.F., J.D., J.K., R.G. and D.S.H. were investigators for the AMG 510 clinical trial. J.C., J.R.L., V.J.C., A.Y.S. and K.R. wrote the paper with contributions from all authors.
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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.
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Extended data figures and tables
Extended Data Fig. 1 Enhanced binding of AMG 510 to KRAS(G12C) results in improved properties.
a, X-ray co-crystal structure of KRAS(G12C/C51S/C80L/C118S) bound to GDP and ARS-1620 (PDB: 5V9U). b, Overlay of ARS-1620 and AMG 510. The right side shows different orientations of His95 (H95) depending on the ligand. c, Biochemical activity of AMG 510 and ARS-1620 in a nucleotide-exchange assay with purified KRAS(G12C/C118A) or KRAS(C118A) protein. Data are mean ± s.d., n = 4 replicates. The wild-type cysteine at position 118 was changed to alanine to avoid reactivity with non-Cys12 cysteines. d, Biochemical activity of AMG 510 and its non-reactive propionamide analogue in a nucleotide-exchange assay with purified KRAS(G12C/C118A); propionamide, mean of n = 2 replicates. e, Kinetic properties of AMG 510 and ARS-1620 as determined by mass spectrometry. f, Calculated maximal reaction rates (kinact or kobs) and the concentrations that achieve a half-maximal rate (KI or [I]50) of AMG 510 and ARS-1620. e, f, kobs, KI, [I]50 and standard error of the curve were determined from nonlinear curve fitting of experimental values. g, h, Inhibition of p-ERK after a 2-h treatment (g; mean, n = 2 replicates) and effects on cell viability after 72-h treatment (h; mean ± s.d., n = 3 replicates) with AMG 510 or ARS-1620.
Extended Data Fig. 2 AMG 510 inhibits KRAS(G12C) signalling and impairs viability.
a, Inhibition of p-ERK with RMC-4550 in NCI-H358 cells. Data are mean ± s.d., n = 3 replicates. b, c, Effect on cellular signalling in NCI-H358 or MIA PaCa-2 after 4- or 24-h treatment with a serial titration of AMG 510 (b) or treatment with 0.1 μM AMG 510 at time points for up to 24 h (c). Top arrow, AMG 510–KRAS(G12C) covalent adduct; bottom arrow, KRAS. Data are from a single experiment (Supplementary Fig. 1). d, Effect of 72-h treatment with AMG 510 on cell viability in adherent monolayer or spheroid culture conditions (mean, n = 2 replicates).
Extended Data Fig. 3 AMG 510 covalently modifies KRAS(G12C) in tumours and inhibits signalling in vivo.
a–d, Mice bearing MIA PaCa-2 T2 (a, c, d) or CT-26 KRASG12C (b) tumours were treated orally with a single dose of vehicle (black bars) or with the indicated doses of AMG 510 (blue bars). Tumours were collected 2 h later (a, b) or over time as indicated (c, d) and levels of p-ERK were measured. AMG 510 concentrations in plasma (red triangles) or tumours (black open circles). Data are mean ± s.e.m., n = 3 mice per group; ****P < 0.0001, ***P < 0.001, **P < 0.01 compared with vehicle; one-way ANOVA followed by Dunnett’s multiple-comparison test. e, Half-life determination of KRAS(G12C) in MIA PaCa-2 and NCI-H358 cells by SILAC. Data are mean ± s.d., n = 3 replicates. f, g, AMG 510 treatment results in covalent modification of KRAS(G12C) that inversely correlates with p-ERK inhibition in MIA PaCa-2 T2 tumours. Data are mean ± s.d., n = 3 mice per group.
Extended Data Fig. 4 AMG 510 inhibits tumour growth of patient-derived xenografts, and exposure to AMG 510 at or above cellular IC90 drives regression of xenografts.
a, Mice bearing MIA PaCa-2 T2 tumours were treated with ARS-1620 at the indicated doses. Data are mean ± s.e.m., n = 10 mice per group; ****P < 0.0001, ***P < 0.001, *P < 0.05 compared with vehicle; repeated-measures ANOVA followed by Dunnett’s multiple-comparison test. #P < 0.05 regression by two-sided Student’s t-test. b, c, Plasma levels of AMG 510 from MIA PaCa-2 T2 or NCI-H358 xenografts. The dotted line represents the p-ERK IC90 values in cells after treatment with AMG 510 for 2 h. d, e, Effect of AMG 510 treatment on tumour growth in KRASG12C small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) PDX models (d) or a SW480-1AC xenograft model (e). Data are mean ± s.e.m., n = 10 mice per group. ****P < 0.0001 compared with vehicle; repeated-measures ANOVA followed by Dunnett’s multiple-comparison test. f, Plasma levels of AMG 510 from CT-26 KRASG12C tumour model. The dotted line represents the p-ERK IC90 values in cells after treatment with AMG 510 for 2 h. g, Individual CT-26 KRASG12C tumour plots of BALB/c nude mice (n = 10) treated with AMG 510 (200 mg kg−1).
Extended Data Fig. 5 Clinical activity of AMG 510 in patients with lung cancer in a first-in-human dose-escalation study.
Computed tomography scans of two patients with KRASG12C lung carcinoma who were treated with AMG 510. Additional representative pre-treatment (baseline) and post-treatment (Rx) scans of patients described in Fig. 3 (left, 180 mg; right, 360 mg). Lesions are denoted by red outline or red arrows. Left images show, from top to bottom, the lung upper left lobe, lung lower left lobe, lung upper left lobe and lung upper left lobe. Right images show, from top to bottom, the lung lower left lobe, lung lower left lobe and adrenal gland. Lesions in the 18-week scans of the patient who was treated with 360 mg AMG 510 were considered too small to accurately measure.
Extended Data Fig. 6 AMG 510 combines with targeted and chemotherapeutic agents, resulting in the synergistic killing of tumour cells and enhanced anti-tumour activity.
a, Growth inhibition matrices and Loewe additivity excess of AMG 510 added in combination with targeted agents to the indicated cell line, with darker colours denoting greater cell killing (growth inhibition) and stronger synergistic interactions (Loewe excess). The maximum tested concentration of the inhibitors and the dose range covered by the matrices for each combination are listed in Supplementary Table 3. b, AMG 510 in combination with carboplatin in NCI-H358 tumour xenografts. Data are mean ± s.e.m., n = 10 mice per group; ****P < 0.0001 compared with vehicle; repeated-measures ANOVA followed by Dunnett’s multiple comparison test; #P < 0.001 regression by two-sided Student’s t-test.
Extended Data Fig. 7 AMG 510 inhibits KRAS(G12C) signalling and viability of syngeneic CT-26 KRASG12C cells.
a, b, Cellular activity of AMG 510 and the MEK inhibitor trametinib in CT-26 KRASG12C and parental CT-26 cell lines as measured by the inhibition of p-ERK after a 2-h treatment (a; mean ± s.d., n = 3 replicates; except trametinib in CT-26, mean of n = 2 replicates) and the effects on cell viability after 72-h treatment in spheroid culture (b; AMG 510 in CT-26 KRASG12C, mean ± s.d., n = 3 replicates; all others, mean of n = 2 replicates).
Extended Data Fig. 8 AMG 510 treatment induces a pro-inflammatory tumour microenvironment.
a, CT-26 KRASG12C tumours were immunophenotyped by flow cytometry. Data are mean ± s.d., n = 8 mice per group; ****P < 0.0001, *P < 0.05; NS, not significant; one-way ANOVA followed by Tukey’s multiple-comparison test. MEKi, MEK inhibitor. b, Mice bearing CT-26 KRASG12C tumours were treated orally with a single dose of vehicle (black bar) or with the indicated dose of MEK inhibitor (blue bar). Tumours were collected 2 h later and levels of p-ERK were measured. MEK inhibitor concentrations in plasma (red triangle) or tumours (black open circle). Data are mean ± s.e.m., n = 3 mice per group; ****P < 0.0001 compared with vehicle; one-way ANOVA followed by Dunnett’s multiple-comparison test. c, Mice bearing CT-26 KRASG12C tumours were treated with MEK inhibitor at the indicated doses. Data are mean ± s.e.m., n = 8 mice per group; **** P < 0.0001 compared with vehicle; repeated-measures ANOVA followed by Dunnett’s multiple comparison test. d, Tumour volumes from the immunophenotyping study (a) of CT-26 KRASG12C tumour-bearing mice treated over 4 days. n = 8 mice per group. e, RNA was isolated from CT-26 KRASG12C tumours. n = 5 mice per group. Gene expression and scores were calculated by nSolver v.4.0. Data are mean ± s.d.; ****P < 0.0001, ***P < 0.001, ** P < 0.01, *P < 0.05; NS, not significant; one-way ANOVA followed by Tukey’s test.
Extended Data Fig. 9 AMG 510 induces expression of chemokines and MHC class I antigens in CT-26 KRASG12C cells.
a, Quantification of Cxcl10 or Cxcl11 transcripts, as well as secreted CXCL10 (IP-10) protein, after 24-h treatment of parental CT-26 or CT-26 KRASG12C cells with AMG 510 or MEK inhibitor. Data are mean ± s.d., n = 4 replicates; ****P < 0.0001, ***P < 0.001, **P < 0.01; NS, not significant; two-way ANOVA followed by Tukey’s multiple-comparison test. b, Ova-pulsed bone-marrow-derived dendritic cells and CellTrace Violet (CTV)-labelled OT-I CD8+ T cells co-cultured with AMG 510 or MEK inhibitor. T cell proliferation was assessed by measuring CTV dilution in T cells. Left, T cells treated with mock (shaded), AMG 510 (solid line) or MEK inhibitor (dashed line) from a representative experiment. Right, data from four independent experiments were pooled and show the frequency of dividing T cells relative to mock treatment. Data are mean ± s.e.m.; **P < 0.01; NS, not significant; one-way ANOVA followed by Tukey’s multiple-comparison test. c, Cell surface expression of MHC class I antigens (H-2Dd and H-2Ld) on CT-26 KRASG12C cells after 24-h treatment with AMG 510 with or without IFNγ as measured by flow cytometry. d, Growth curves of either CT-26 or CT-26 KRASG12C tumours in BALB/c mice (n = 15).
Supplementary information
Supplementary Information
This file contains Methods; Statistics and Reproducibility; Supplementary Table 1 – Cellular assay data; Supplementary Table 2 legend; Supplementary Table 3 – AMG 510 combination matrices and synergy scores; Supplementary Table 4 – Chemokine / receptor gene expression in CT-26 KRAS p.G12C tumours following AMG 510 treatment; Supplementary Table 5 – Antibodies for immunoblotting, immunohistochemistry, and flow cytometry; Supplementary Table 6 legend; Supplementary Figure 1 – Immunoblot source images for Extended Data Fig. 2b, c; Supplementary Figures 2-4 – Gating strategies for flow cytometry experiments; and Supplementary References.
Supplementary Table
Supplementary Table 2: NCI-H358 cysteine proteome analysis. Identification and quantitation of desthiobiotinylated peptides was obtained using database searching via a custom informatics pipeline developed in the Gygi Lab at Harvard Medical School that utilizes SEQUEST. Database search parameters are included in the accompanying Excel file. Log2 fold changes were calculated between DMSO control and AMG 510-treated sample groups (n=5/group), and a two-tailed t test for each peptide was performed to assess the statistical significance of difference between treated and DMSO control sample groups assuming equal variance.
Supplementary Table
Supplementary Table 6: Gene expression pathway score analysis. Pathway scores (interferon score, antigen processing score, chemokine and receptors score, MHC score, TLR score, and T Cell function score) and cell profiling scores (NK cell score, cytotoxic cell score, and CD45 score) were generated by nSolver Advanced Analysis (NanoString Technologies). The genes included in each score, p values used to calculate pathway and cell profiling scores, and the statistical method used by nSolver Advanced Analysis v2.0.115 to determine p values are listed in the accompanying Excel file.
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Canon, J., Rex, K., Saiki, A.Y. et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature 575, 217–223 (2019). https://doi.org/10.1038/s41586-019-1694-1
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DOI: https://doi.org/10.1038/s41586-019-1694-1
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