Dataset Information

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

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.

SUBMITTER: Nakayama A

PROVIDER: S-EPMC8888662 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Publications

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

Nakayama Ayako A Nagashima Takeyuki T Nishizono Yoshihiro Y Kuramoto Kazuyuki K Mori Kenichi K Homboh Kazuya K Yuri Masatoshi M Shimazaki Masashi M

British journal of cancer 20211118 5

<h4>Background</h4>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.<h4>Methods</h4>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 xen ...[more]

PMID: 34795410

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Project description:The identification of molecules that can bind covalently to KRAS G12C and lock it in an inactive GDP-bound conformation has opened the door to targeting KRAS G12C selectively. These agents have shown promise in preclinical tumor models and clinical trials. FDA has recently granted approval to sotorasib for KRAS G12C mutated non-small cell lung cancer (NSCLC). However, patients receiving these agents as monotherapy generally develop drug resistance over time. This necessitates the development of multi-targeted approaches that can potentially sensitize tumors to KRAS inhibitors. We generated KRAS G12C inhibitor-resistant cell lines and observed that they exhibit sensitivity toward selinexor, a selective inhibitor of nuclear export protein exportin1 (XPO1), as a single agent. KRAS G12C inhibitors in combination with selinexor suppressed the proliferation of KRAS G12C mutant cancer cell lines in a synergistic manner. Moreover, combined treatment of selinexor with KRAS G12C inhibitors resulted in enhanced spheroid disintegration, reduction in the number and size of colonies formed by G12C mutant cancer cells. Mechanistically, the combination of selinexor with KRAS G12C inhibitors suppressed cell growth signaling and downregulated the expression of cell cycle markers, KRAS and NF-kB as well as increased nuclear accumulation of tumor suppressor protein Rb. In an in vivo KRAS G12C cell-derived xenograft model, oral administration of a combination of selinexor and sotorasib was demonstrated to reduce tumor burden and enhance survival. In conclusion, we have shown that the nuclear transport protein XPO1 inhibitor can enhance the anticancer activity of KRAS G12C inhibitors in preclinical cancer models.SignificanceIn this study, combining nuclear transport inhibitor selinexor with KRAS G12C inhibitors has resulted in potent antitumor effects in preclinical cancer models. This can be an effective combination therapy for cancer patients that do not respond or develop resistance to KRAS G12C inhibitor treatment.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

Similar Datasets

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