Abstract C097: KRASG12C exhibits allele-specific biology in pancreatic cancer and targeting CD24 sensitizes KRASG12C-driven tumors to sotorasib treatment
Authors: Wei Yongkun , Liu Minghui , Nguyen Phuoc T. , Pan Dean N. , Yao Wantong , Ying Haoqiang 
Published: January 2024

Abstract
Pancreatic adenocarcinoma (PDAC) is predominantly driven by KRAS oncogene. While all oncogenic KRAS mutations result in its hyperactivation, the allele-specific biology of KRAS mutations remain poorly understood. Addressing such issues has become particularly important with the recent advancements in the development of allele-specific and pan-KRAS inhibitors. Among the KRAS inhibitors, KRASG12C inhibitors (G12Ci), Sotorasib and Adagrasib, have been approved for treating KRASG12C-mutant lung cancer. Sotorasib also exhibited promising anticancer activity in human PDAC, with 21% response rate and over 70% patients experiencing certain level of tumor control. However, targeting KRAS oncogenes faces the major challenge of therapy resistance, which severely limited its survival benefit. While multiple studies have elucidated potential resistance mechanisms to G12Ci in lung cancer, the molecular mechanisms underlying its resistance in PDAC remains elusive, largely owing to the scarcity of relevant and faithful preclinical models. Here, we report the generation of a new autochthonous KRASG12C-driven PDAC model (p48Cre; LSL-KrasG12C; p53L/+, KCPC). Compared to the KRASG12D-driven KPC model (p48Cre; LSL-KrasG12D; p53L/+), tumor development in KCPC model is significantly delayed accompanied with corresponding decrease in both KRAS signaling and proliferation in premalignant lesions. As a result, the overall survival of the KCPC model is significantly prolonged compared to the KPC model, indicating allele-specific discrepancy of KRAS mutations during PDAC initiation. However, upon malignant progression, KRASG12C-driven mouse PDAC exhibit similar histopathological and molecular features as KRASG12D-driven tumors. Furthermore, similar to the clinical observation, KCPC tumors exhibit only partial response to Sotorasib treatment. CyTOF analysis indicates that such tumor persistence following G12Ci treatment occurs even in the presence of conversion from a ‘cold’ pro-tumor immune microenvironment to a ‘hot’ anti-tumor immune environment, as evidenced by the prominent increase in both cytotoxic T cells and M1-like macrophages. Interestingly, we discovered that the expression of CD24, which was recently identified as a new ‘do not eat me’ signal, is significantly upregulated on the surface of persist tumor cells, which suppresses the function of anti-tumor macrophages. Treatment with anti-CD24 blocking mAb enhanced macrophage-mediated phagocytosis in vitro and significantly sensitizes KCPC-derived xenograft tumors to Sotorasib treatment in vivo in a macrophage-dependent manner. Similar upregulation of CD24 following KRAS inhibition and therapeutic benefit of co-targeting CD24 and KRAS were also observed in KRASG12D-driven mouse and human PDAC, implicating the potential of such combination in a broader spectrum of KRAS-driven PDAC. Together, our findings revealed the allele-specific function of KRASG12C in the development of PDAC and identified a novel immune combination to improve the outcome of KRAS targeted therapy in PDAC.
Citation Format: Yongkun Wei, Minghui Liu, Phuoc T. Nguyen, Dean N. Pan, Wantong Yao, Haoqiang Ying. KRASG12C exhibits allele-specific biology in pancreatic cancer and targeting CD24 sensitizes KRASG12C-driven tumors to sotorasib treatment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C097.