Taş İsa, Jacobs Ruben, Albrecht Juliane, Barrientos Sebastian A, Åberg Josephine, Sime Wondossen, Brunnström Hans, Persson Helena, Kazi Julhash U, Massoumi Ramin
Department of Laboratory Medicine, Division of Translational Cancer Research, Lund University, Lund, Sweden.
Department of Clinical Sciences Lund, Division of Oncology, Lund University, Lund, Sweden.
J Exp Clin Cancer Res. 2025 Apr 24;44(1):128. doi: 10.1186/s13046-025-03385-9.
Lung cancer remains one of the most challenging diseases to treat due to its heterogeneity. Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) mutations are genetic drivers in numerous cancer types including lung adenocarcinoma (LUAD). Despite recent advances in KRAS-targeted therapies, treatment resistance and limited therapeutic options necessitate advanced preclinical models, such as organoids, to identify personalized cancer therapies by screening novel therapeutic strategies and synergistic drug combinations.
We established LUAD in genetically engineered mouse (GEM) models of Kras & Trp53 (KP) and KP with Ctnnb1 mutation (KPC). Tumor-derived organoids from these models recapitulated the genomic landscape and histopathological characteristics of their parental tumors. The organoids displayed tumorigenic potential when implanted in immunocompromised mice, forming tumors in contrast to unlike healthy lung-derived organoids. Drug screening identified effective kinase inhibitors and DNA methyltransferase (DNMT) inhibitors against the organoids. Notably, the combination of these drugs exhibited the highest synergy in KPC organoids.
We successfully developed LUAD organoids harboring Kras mutations and identified multiple potential therapeutic agents targeting these cells. Furthermore, we demonstrated the effectiveness of a DNMT inhibitor-based combination therapy, presenting a promising strategy for this challenging lung cancer subtype.
由于肺癌具有异质性，它仍然是最难治疗的疾病之一。 Kirsten大鼠肉瘤病毒癌基因同源物（KRAS）突变是包括肺腺癌（LUAD）在内的多种癌症类型的遗传驱动因素。尽管KRAS靶向治疗最近取得了进展，但治疗耐药性和有限的治疗选择需要先进的临床前模型，如类器官，通过筛选新的治疗策略和协同药物组合来确定个性化的癌症治疗方法。
我们在Kras和Trp53（KP）以及带有Ctnnb1突变的KP（KPC）的基因工程小鼠（GEM）模型中建立了LUAD。来自这些模型的肿瘤衍生类器官重现了其亲本肿瘤的基因组格局和组织病理学特征。当植入免疫缺陷小鼠体内时，这些类器官显示出致瘤潜力，与健康肺衍生的类器官不同，它们会形成肿瘤。药物筛选确定了针对类器官的有效激酶抑制剂和DNA甲基转移酶（DNMT）抑制剂。值得注意的是，这些药物的组合在KPC类器官中表现出最高的协同作用。
我们成功地开发了携带Kras突变的LUAD类器官，并确定了多种针对这些细胞的潜在治疗药物。此外，我们证明了基于DNMT抑制剂的联合治疗的有效性，为这种具有挑战性的肺癌亚型提供了一种有前景的策略。
