An Allele Agnostic Mutant KRAS Inhibitor Demonstrates Broad Spectrum Tumour Growth Inhibition in Pancreatic Ductal Adenocarcinoma

KRAS is among the most frequently mutated oncogenes in cancer, and for decades, efforts at pharmacological blockade of its function in solid cancers have been unsuccessful. A notable advance in this endeavor is the recent development of small molecule KRAS inhibitors, which enable direct targeting of the mutant oncoprotein. Here, we comprehensively evaluate the pre-clinical efficacy of BI-2493 (henceforth, “panKRASi”), a first-in-class allele agnostic mutant KRAS inhibitor, in pancreatic ductal adenocarcinoma (PDAC). We report effective tumor growth suppression across a broad range of models, including cell lines, organoids, patient-derived xenografts (PDXs), syngeneic orthotopic models, and prolonged survival in genetically engineered mouse models. Overall, transcriptomic, proteomic, and phospho-proteomic profiling of panKRASi-treated models confirms robust Ras pathway inhibition, along with the sustained regulation of crucial hallmarks essential for tumor maintenance. In panKRASi-treated immune-replete models, we observe increased intratumoral CD8+ effector T cells and decreased infiltration of myeloid cells, along with remodeling of the tumor microenvironment (TME). In the long-term, emergence of resistance to panKRASi monotherapy is associated with increased YAP and MYC signaling within tumor cells, and enhanced expression of immune checkpoints within the TME that impede effective T-cell function and changes in cell composition. Our multifaceted approach identifies potential combinatorial approaches for generating sustained responses to panKRASi. Overall design: KPPC GEMM (LSL-KRASG12D; Trp53loxP/loxP; Pdx1-Cre) PDAC models. were treated with vehicle, or panKRASi (BI2493, 90 mg/kg) for the indicated timeframes. 1 pancreata/tumor was included per sample.

KRAS是癌症中最常见的突变癌基因之一，数十年来，针对实体瘤中KRAS功能的药理学阻断研究均未取得成功。该领域的一项重要突破是近年来小分子KRAS抑制剂的研发，这类药物可直接靶向突变型癌蛋白。本研究全面评估了首个人类等位基因不依赖性突变KRAS抑制剂BI-2493（以下简称“泛KRAS抑制剂（panKRASi）”）在胰腺导管腺癌（PDAC）中的临床前疗效。我们在多种模型中均观察到显著的肿瘤生长抑制效果，涵盖细胞系、类器官、患者来源异种移植瘤（PDXs）、同基因原位模型，并且在基因工程小鼠模型中实现了生存期的显著延长。

总体而言，对泛KRAS抑制剂处理的模型进行转录组学、蛋白质组学及磷酸化蛋白质组学分析证实，Ras通路受到强效抑制，同时肿瘤维持所必需的关键标志性通路的调控也持续稳定。

在免疫健全的泛KRAS抑制剂处理模型中，我们观察到瘤内CD8+效应T细胞浸润增加、髓系细胞浸润减少，同时肿瘤微环境（TME）发生重塑。

长期来看，泛KRAS抑制剂单药治疗的耐药性出现与肿瘤细胞内YAP和MYC信号通路激活增强相关，同时肿瘤微环境中免疫检查点的表达上调，这会阻碍T细胞的有效功能并改变细胞组成。我们的多维度研究方法为制定可持续响应泛KRAS抑制剂的联合治疗方案提供了潜在方向。

总体实验设计：采用KPPC基因工程小鼠模型（LSL-KRASG12D; Trp53loxP/loxP; Pdx1-Cre）构建的PDAC模型，分别给予赋形剂对照或泛KRAS抑制剂（BI2493，90 mg/kg）处理指定时长。每份样本对应1个胰腺/肿瘤组织。