Abstract 3921: Development of a KRAS-G12C-driven pancreatic cancer mouse model

Abstract KRASG12C inhibitor (G12Ci) has produced encouraging, albeit mild clinical benefit in pancreatic ductal adenocarcinoma (PDAC). Identifying and targeting resistance mechanisms to G12Ci treatment remains the major challenge due to the lack of faithful preclinical models. To better understand the tumor biology of the KRASG12C allele, we established a mouse model engineered with the LSL-KrasG12C, conditional p53 knockout (p53L), and pancreatic-specific p48-Cre alleles. The resulting p48-Cre LSL-KrasG12C p53L/+ (KCPC) mice exhibit decreased number and area of PanIN/ADM lesions compared to age-matched KrasG12D-driven controls (KDPC). The decreased neoplastic activity of KrasG12C aligns with decreased downstream signaling (phospho-ERK and phospho-AKT) and cell proliferation (Ki67) in premalignant epithelial cells, suggesting that KRASG12C is a less potent oncogenic allele compared to KRASG12D. Compared to KRASG12D, KRASG12C failed to induce complete ADM which is characterized with the transdifferentiating of acinar cells into progenitor-like ductal cells. The tumor microenvironment of KCPC mice is less immunosuppressive than that of KDPC, which may partially explain the slower progression of KCPC tumor. The relatively weak tumor development in KCPC model results in significantly prolonged median overall survival compared to KDPC model. Histopathology analysis of advanced tumors from the KCPC model revealed similar histological features of ductal adenocarcinoma compared to KDPC model or human PDAC. As for KRAS downstream signaling, PDAC lesions from the KCPC and KDPC models exhibited similar phospho-ERK, phospho-MEK and phospho-S6K1. Both the total KRAS level and the amount of active form of KRAS are also comparable between the two groups. Interestingly, phospho-AKT level was lower in KCPC than in the KDPC tumor cells. Together, our data indicates that, while KRASG12C-driven PDAC premalignant lesions exhibit distinctive molecular features compared to the KRASG12D-driven ones, there is no obvious cellular or molecular difference between the two KRAS genotypes once the tumor progresses to an advanced stage. Citation Format: Yongkun Wei, Minghui Liu, Er-Yen Yen, Jun Yao, Phuoc T. Nguyen, Xiaofei Wang, Zecheng Yang, Dean N. Pan, Jangho Park, Yiming Cai, Andrea Viale, Huamin Wang, Dan Zhao, Ronald A. DePinho, Wantong Yao, Haoqiang Ying. Development of a KRAS-G12C-driven pancreatic cancer mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3921.