Advanced organoid models for targeting Kras-driven lung adenocarcinoma in drug discovery and combination therapy
Year: 2025
Type: article
Abstract: BACKGROUND: 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. RESULTS: 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. CONCLUSION: 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.
Authors: İsa Taş, Ruben Jacobs, Juliane Albrecht, Sebastian A. Barrientos, Josephine Åberg, Wondossen Sime, Hans Brunnström, Helena Persson, Julhash U. Kazi, Ramin Massoumi
Institutions: Lund University, Medicon Village
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,190
OpenAlex ID: W4409771810