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Background <p>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.</p> Results <p>We established LUAD in genetically engineered mouse (GEM) models of <i>Kras</i><sup>G12V</sup> &amp; <i>Trp53</i> <sup>Δex2−10</sup> (KP) and KP with <i>Ctnnb1</i><sup>Δex3</sup> 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.</p> Conclusion <p>We successfully developed LUAD organoids harboring <i>Kras</i> 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.</p>

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Advanced organoid models for targeting Kras-driven lung adenocarcinoma in drug discovery and combination therapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月24日

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  • İsa Taş,
  • Ruben Jacobs,
  • Juliane Albrecht,
  • Sebastian A. Barrientos,
  • Josephine Åberg,
  • Wondossen Sime,
  • Hans Brunnström,
  • Helena Persson,
  • Julhash U. Kazi,
  • Ramin Massoumi

摘要

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.