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Advanced organoid models for targeting Kras-driven lung adenocarcinoma in drug discovery and combination therapy
İsa Taş1, Ruben Jacobs1, Juliane Albrecht2
1Department of Laboratory Medicine, Division of Translational Cancer Research, Lund University, Lund, Sweden.
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:
We established LUAD in genetically engineered mouse (GEM) models of KrasG12V & Trp53 Δex2-10 (KP) and KP with Ctnnb1Δex3 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.
Insights
Researchers developed lung adenocarcinoma organoids from genetically engineered mouse models with KRAS mutations. These organoids show promise for testing new therapies, especially combination treatments involving DNA methyltransferase inhibitors.
Area of Science:
- Oncology
- Genetics
- Drug Discovery
Background:
- Lung adenocarcinoma (LUAD) is heterogeneous and challenging to treat.
- KRAS mutations are key drivers in LUAD, but resistance to targeted therapies is common.
- Advanced preclinical models like organoids are needed for personalized therapy development.
Purpose of the Study:
- To establish and characterize LUAD organoids from genetically engineered mouse models (GEMMs) harboring Kras mutations.
- To evaluate the potential of these organoids as preclinical models for drug screening.
- To identify effective therapeutic strategies, including synergistic drug combinations, for Kras-mutated LUAD.
Main Methods:
- Generation of LUAD GEMMs with Kras and Trp53 mutations (KP) and additional Ctnnb1 mutation (KPC).
- Establishment and characterization of tumor-derived organoids from KP and KPC models.
- Assessment of organoid tumorigenicity in vivo and drug screening using kinase inhibitors and DNMT inhibitors.
Main Results:
- LUAD organoids accurately recapitulated the genomic and histopathological features of parental tumors.
- Organoids demonstrated tumorigenic potential upon implantation, unlike healthy lung organoids.
- Kinase inhibitors and DNMT inhibitors showed efficacy against LUAD organoids, with notable synergy observed for the combination in KPC organoids.
Conclusions:
- Successfully developed functional LUAD organoids harboring Kras mutations.
- Identified potential therapeutic agents and synergistic drug combinations for Kras-mutated LUAD.
- A DNMT inhibitor-based combination therapy presents a promising strategy for this LUAD subtype.
