Abstract 5735: 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

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.

KRAS G12C inhibitor combination therapies: current evidence and challenge

“…ASP3082 is a protein degrader that connects mutated KRAS G12D with E3 ligase to initiate the degradation process through ubiquitination. An in vivo study demonstrated its anti-tumor efficacy in PDAC, CRC, and NSCLC models ( 97 ). A phase I trial of ASP3082 is currently ongoing (NCT05382559).…”

Targeting KRAS in Pancreatic Ductal Adenocarcinoma: The Long Road to Cure

“…The binding of the PROTAC to both molecules targets the protein of interest to ubiquitination and subsequent degradation by the ubiquitin-proteasome system. ASP3082 (Astellas Pharma) is a degrader that binds to both KRAS G12D and E3 ubiquitin ligase, fostering KRAS G12D degradation [125]. Preclinical data suggest significant activity against pancreatic cancer in xenograft mouse models of PDAC.…”