In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 5735-5735
Abstract:
KRAS is one of the most frequently mutated oncogenes in various cancers. Among KRAS mutations, KRAS G12D is the most frequent driver mutation and is found in approximately 34% of patients with pancreatic ductal adenocarcinoma (PDAC), 12% of patients with colorectal cancer (CRC), 4% of patients with lung adenocarcinoma, and in a subset of patients with other solid tumors. We have identified ASP3082 as a novel KRAS G12D degrader with high potency and selectivity. Here, we have evaluated in vivo antitumor activities and pharmacodynamic properties of ASP3082 in various KRAS G12D-mutated xenograft models. ASP3082 was intravenously administered to KRAS G12D-mutated cancer-xenograft-bearing mice, and plasma and tumors were collected at defined time points. The drug concentration and KRAS-related signal transduction were measured in the xenograft model. The in vivo efficacy of ASP3082 monotherapy was confirmed in multiple xenograft mouse models following intravenous administration. Once-weekly intravenous administration of ASP3082 induced dose-dependent and significant growth inhibition of KRAS G12D PDAC tumors, resulting in profound tumor regression without body weight loss. ASP3082 showed sustained concentrations in the xenograft tumors after a single intravenous administration and decreased KRAS G12D-mutated-protein levels according to the duration of the sustained ASP3082 concentrations. ASP3082 also demonstrated marked inhibition of extracellular signal-regulated kinase phosphorylation and its downstream genes, and potently induced cleavage of caspase 3. In addition, ASP3082 exhibited potent antitumor activities in not only PDAC but also CRC and non-small cell lung cancer KRAS G12D-mutated mouse models. These studies demonstrated that ASP3082 induced degradation of KRAS G12D protein, inhibition of KRAS downstream molecules, and an apoptotic response to show dose-dependent antitumor activity in multiple KRAS G12D-mutated cancer models. ASP3082 is a potential therapeutic agent for patients with tumors harboring the KRAS G12D mutation. Currently, a phase 1 clinical trial is underway in patients with previously treated, locally advanced or metastatic solid tumors with KRAS G12D mutation (NCT05382559). Citation Format: Takeyuki Nagashima, Tomohiro Yoshinari, Yoshihiro Nishizono, Mamoru Tasaki, Kohei Inamura, Hiroki Ishioka, Atsushi Suzuki, Fumio Osaki, Yosuke Yamanaka, Masahiko Hayakawa. Novel KRAS G12D degrader ASP3082 demonstrates in vivo, dose-dependent KRAS degradation, KRAS pathway inhibition, and antitumor efficacy in multiple KRAS G12D-mutated cancer models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5735.
Type of Medium:
Online Resource
ISSN:
1538-7445
DOI:
10.1158/1538-7445.AM2023-5735
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2023
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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