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

Taş, İsa LU ; Jacobs, Ruben LU ; Albrecht, Juliane LU orcid ; Barrientos, Sebastian A LU orcid ; Åberg, Josephine LU ; Sime, Wondossen LU ; Brunnström, Hans LU orcid ; Persson, Helena LU orcid ; Kazi, Julhash U LU orcid and Massoumi, Ramin LU (2025) In Journal of Experimental and Clinical Cancer Research 44.
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: 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... (More)

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.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Animals, Organoids/drug effects, Mice, Proto-Oncogene Proteins p21(ras)/genetics, Adenocarcinoma of Lung/drug therapy, Humans, Drug Discovery/methods, Lung Neoplasms/drug therapy, Disease Models, Animal, Mutation, Antineoplastic Combined Chemotherapy Protocols/pharmacology
in
Journal of Experimental and Clinical Cancer Research
volume
44
article number
128
pages
19 pages
publisher
BioMed Central (BMC)
external identifiers
  • scopus:105003478193
  • pmid:40275403
ISSN
1756-9966
DOI
10.1186/s13046-025-03385-9
language
English
LU publication?
yes
additional info
© 2025. The Author(s).
id
837b72e8-1a58-4f64-9bb4-2cfeb10fb699
date added to LUP
2025-04-30 10:44:49
date last changed
2025-05-01 04:02:22
@article{837b72e8-1a58-4f64-9bb4-2cfeb10fb699,
  abstract     = {{<p>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.</p><p>RESULTS: We established LUAD in genetically engineered mouse (GEM) models of KrasG12V &amp; 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.</p><p>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.</p>}},
  author       = {{Taş, İsa and Jacobs, Ruben and Albrecht, Juliane and Barrientos, Sebastian A and Åberg, Josephine and Sime, Wondossen and Brunnström, Hans and Persson, Helena and Kazi, Julhash U and Massoumi, Ramin}},
  issn         = {{1756-9966}},
  keywords     = {{Animals; Organoids/drug effects; Mice; Proto-Oncogene Proteins p21(ras)/genetics; Adenocarcinoma of Lung/drug therapy; Humans; Drug Discovery/methods; Lung Neoplasms/drug therapy; Disease Models, Animal; Mutation; Antineoplastic Combined Chemotherapy Protocols/pharmacology}},
  language     = {{eng}},
  month        = {{04}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Journal of Experimental and Clinical Cancer Research}},
  title        = {{Advanced organoid models for targeting Kras-driven lung adenocarcinoma in drug discovery and combination therapy}},
  url          = {{http://dx.doi.org/10.1186/s13046-025-03385-9}},
  doi          = {{10.1186/s13046-025-03385-9}},
  volume       = {{44}},
  year         = {{2025}},
}