Xiao Jeffrey, Kim Joshua, Park Brandon, Baylink David J, Kwon Cedric, Tran Victoria, Lee Scott, Codorniz Kevin, Tan Laren, Moreno Pamela Lobo, Schill-Depew Amy, Mirshahidi Saied, De Semir David, Hanna Diana, Naqvi Kiran, Cao Huynh, Chen Chien-Shing, Xiu Joanne, Lenz Heinz-Josef, Mirshahidi Hamid, Reeves Mark E, Xu Yi
Division of Discovery, Innovation and Regenerative Medicine, Department of Medicine, School of Medicine, Loma Linda University, Loma Linda, 92354, CA, USA.
Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, School of Medicine, Loma Linda University, Loma Linda, 92354, CA, USA.
Exp Hematol Oncol. 2025 May 26;14(1):79. doi: 10.1186/s40164-025-00669-w.
Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with a 5-year overall survival (OS) rate of approximately 12%. More than 90% of PDAC patients harbor oncogenic mutations in the Kirsten rat sarcoma viral homolog (KRAS) gene. MRTX1133 (MRTX), a novel inhibitor of KRAS (the most common KRAS mutation found in pancreatic and colon cancers) has shown promise as a therapeutic agent. To address reported resistance to MRTX, we adapted our anti-leukemia co-targeting strategy and evaluated a combination of MRTX and Bedaquiline (BED), an FDA-approved inhibitor of mitochondrial ATP production, in in vitro human PDAC models. The combination of MRTX and BED demonstrated enhanced cytotoxic effects by disrupting all 11 genes within the DNA helicase family (CMG complex: CDC45-MCM-GINS), which are essential for initiating DNA replication and regulating cell cycle progression. Notably, real-world data analysis from Caris Life Sciences and NCI-TCGA database revealed that low transcriptomic expression of the DNA helicase CMG complex was significantly associated with prolonged survival (e.g., low CDC45 expression and low GINS2 expression with greater than 8 months longer overall survival) in PDAC patients with KRAS mutations (N = 9,717; P < 0.00001). However, this combination therapy also triggered strong pro-survival nuclear reprogramming. This effect was mediated by significant genetic activation of an NFκB2-DDIT (DNA damage-induced transcript) axis, which supported tumor chromosomal integrity and DNA repair mechanisms. To overcome NFκB2-driven resistance mechanisms, we explored a triple-targeting strategy that addresses metabolic and genomic plasticity in addition to actively intercepting cell division. This approach combines MRTX1133, Bedaquiline, and the NFκB2 inhibitor SN52, offering a novel therapeutic avenue to treat aggressive pancreatic cancer and potentially improve patient outcomes.
胰腺导管腺癌（PDAC）是一种极具毁灭性的恶性肿瘤，其5年总生存率（OS）约为12%。超过90%的PDAC患者在 Kirsten 大鼠肉瘤病毒同源物（KRAS）基因中存在致癌突变。MRTX1133（MRTX）是一种新型的KRAS抑制剂（在胰腺癌和结肠癌中发现的最常见的KRAS突变），已显示出作为治疗药物的潜力。为了解决报道的对MRTX的耐药性，我们调整了我们的抗白血病共靶向策略，并在体外人PDAC模型中评估了MRTX与贝达喹啉（BED，一种FDA批准的线粒体ATP生成抑制剂）的联合应用。MRTX和BED的联合应用通过破坏DNA解旋酶家族中的所有11个基因（CMG复合物：CDC45-MCM-GINS）显示出增强的细胞毒性作用，这些基因对于启动DNA复制和调节细胞周期进程至关重要。值得注意的是，来自Caris生命科学公司和NCI-TCGA数据库的真实世界数据分析显示，在KRAS突变的PDAC患者中（N = 9717；P < 0.00001），DNA解旋酶CMG复合物的低转录组表达与延长生存期显著相关（例如，低CDC45表达和低GINS2表达与总生存期延长超过8个月相关）。然而，这种联合疗法也引发了强烈的促生存核重编程。这种效应是由NFκB2-DDIT（DNA损伤诱导转录本）轴的显著基因激活介导的，该轴支持肿瘤染色体完整性和DNA修复机制。为了克服NFκB2驱动的耐药机制，我们探索了一种三靶向策略，除了积极拦截细胞分裂外，还解决代谢和基因组可塑性问题。这种方法结合了MRTX1133、贝达喹啉和NFκB2抑制剂SN52，为治疗侵袭性胰腺癌提供了一种新的治疗途径，并有可能改善患者的预后。
