Actinomycin D and Telmisartan Combination Targets Lung Cancer Stem Cells Through the Wnt/Beta Catenin Pathway

Area of Science:

• Oncology
• Stem Cell Biology
• Drug Discovery

Background:

• Lung cancer treatment failure is often due to drug resistance, with cancer stem cells (CSCs) playing a key role in resistance, metastasis, and relapse.
• Understanding the mechanisms of CSC-driven drug resistance is crucial for developing effective lung cancer therapies.

Purpose of the Study:

• To develop a 3D tumoroid culture system for expanding lung CSCs and screening for novel anti-CSC drugs.
• To identify and evaluate combination therapies targeting both bulk tumor cells and CSCs to overcome drug resistance in lung cancer.

Main Methods:

• Lung cancer cells were cultured on 3D fibrous scaffolds to form tumoroids, mimicking in vivo tumor characteristics and expanding CSCs.
• A library of FDA-approved drugs was screened using tumoroid cultures to identify CSC inhibitors, leading to the selection of Actinomycin D (AD).
• AD was combined with Telmisartan (TS), an angiotensin receptor antagonist with known drug permeability-enhancing and anti-CSC properties, and evaluated in syngeneic and xenograft mouse models.

Main Results:

• The 3D tumoroid system successfully expanded CSCs and served as a platform for drug screening.
• Actinomycin D (AD) was identified as a potent inhibitor of CSCs.
• The combination of AD and Telmisartan (TS) administered intra-tumorally demonstrated significantly enhanced efficacy compared to either drug alone in preclinical mouse models.
• Mechanistic studies indicated that AD + TS treatment reduced active β-catenin signaling, which was associated with CSC expansion.

Conclusions:

• The 3D tumoroid culture system is a valuable tool for expanding CSCs ex vivo and facilitating targeted drug screening for lung cancer.
• The combination of Actinomycin D and Telmisartan represents a promising therapeutic strategy for overcoming drug resistance in metastatic lung cancer.
• This approach holds potential for individualizing treatments for patients with drug-resistant lung cancer by targeting CSCs and their associated signaling pathways.