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Translational Therapeutics

Characterisation of a novel KRAS G12C inhibitor ASP2453 that shows potent anti-tumour activity in KRAS G12C-mutated preclinical models

British Journal of Cancer volume 126, pages 744–753 (2022)Cite this article

Subjects

Abstract

Background

KRAS is one of the most frequently mutated oncogenes in various cancers, and several novel KRAS G12C direct inhibitors are now in clinical trials. Here, we characterised the anti-tumour efficacy of ASP2453, a novel KRAS G12C inhibitor, in preclinical models of KRAS G12C-mutated cancer.

Methods

We evaluated the in vitro and in vivo activity of ASP2453, alone or in combination with targeted agents and immune checkpoint inhibitors, in KRAS G12C-mutated cancer cells and xenograft models. We also assessed pharmacological differences between ASP2453 and AMG 510, another KRAS G12C inhibitor, using an SPR assay, washout experiments and an AMG 510-resistant xenograft model.

Results

ASP2453 potently and selectively inhibited KRAS G12C-mediated growth, KRAS activation and downstream signalling in vitro and in vivo, and improved the anti-tumour effects of targeted agents and immune checkpoint inhibitors. Further, ASP2453 had more rapid binding kinetics to KRAS G12C protein and showed more potent inhibitory effects on KRAS activation and cell proliferation after washout than AMG 510. ASP2453 also induced tumour regression in an AMG 510-resistant xenograft model.

Conclusions

ASP2453 is a potential therapeutic agent for KRAS G12C-mutated cancer. ASP2453 showed efficacy in AMG 510-resistant tumours, even among compounds with the same mode of action.

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Fig. 1: ASP2453 is a potent, selective and covalent KRAS G12C inhibitor.
Fig. 2: ASP2453 selectively inhibits KRAS signalling and proliferation of KRAS G12C-mutated in cancer cells in vitro.
Fig. 3: Oral administration of ASP2453 induces anti-tumour activity in an NCI-H1373 xenograft model.
Fig. 4: ASP2453 shows potent anti-tumour activity in multiple human cancer xenograft models.
Fig. 5: Combination ASP2453 with erlotinib or anti-PD-1 antibody inhibits cell proliferation in vitro and tumour growth in vivo.
Fig. 6: Comparison of ASP2453 and AMG 510 in vitro and in vivo.

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Data availability

Researchers may request access to anonymized participant-level data, trial-level data and protocols from Astellas sponsored clinical trials at www.clinicalstudydatarequest.com. For the Astellas criteria on data sharing see https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Astellas.aspx.

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Acknowledgements

We thank Dr Hirofumi Ishii, Dr Yukinori Shimoshige and Mr Yosuke Yamanaka for support with the biological study. We are grateful to Dr Masahiko Hayakawa and Dr Taku Yoshida for their useful suggestions.

Funding

This study was funded by Astellas Pharma Inc.

Author information

Authors and Affiliations

  1. Drug Discovery Research, Astellas Pharma Inc., Tsukuba-shi, Ibaraki, Japan

    Ayako Nakayama, Takeyuki Nagashima, Yoshihiro Nishizono, Kazuyuki Kuramoto, Kenichi Mori, Kazuya Homboh & Masatoshi Yuri

  2. Astellas Research Institute of America LLC, Northbrook, IL, USA

    Masashi Shimazaki

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  1. Ayako Nakayama
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Contributions

AN, TN and MS conceived the study and designed experiments. AN, YN, TN, MS, KK, KM, KH and MY developed methodology. AN, YN, TN, KK, KM, KH and MY acquired and analysed the data. All authors edited the manuscript and approved the submission of the final version.

Corresponding author

Correspondence to Ayako Nakayama.

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Ethics approval and consent to participate

No human participants, human data or human tissue were used as parts of this study. All animal experimental procedures were approved by the Institutional Animal Care and Use Committee of Astellas Pharma Inc., Tsukuba Research Center, which is accredited by AAALAC International.

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Not applicable.

Competing interests

All authors are employees of Astellas Pharma Inc. and its affiliates.

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Nakayama, A., Nagashima, T., Nishizono, Y. et al. Characterisation of a novel KRAS G12C inhibitor ASP2453 that shows potent anti-tumour activity in KRAS G12C-mutated preclinical models. Br J Cancer 126, 744–753 (2022). https://doi.org/10.1038/s41416-021-01629-x

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