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Published on: July 25, 2020
Targeting SMAD3 Improves Response to Oxaliplatin in Esophageal Adenocarcinoma Models by Impeding DNA Repair
Farah Ballout1, Heng Lu1,2, Nadeem Bhat1
1Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida.
Purpose:
TGFβ signaling is implicated in the progression of most cancers, including esophageal adenocarcinoma (EAC). Emerging evidence indicates that TGFβ signaling is a key factor in the development of resistance toward cancer therapy.
Experimental Design:
In this study, we developed patient-derived organoids and patient-derived xenograft models of EAC and performed bioinformatics analysis combined with functional genetics to investigate the role of SMAD family member 3 (SMAD3) in EAC resistance to oxaliplatin.
Results:
Chemotherapy nonresponding patients showed enrichment of SMAD3 gene expression when compared with responders. In a randomized patient-derived xenograft experiment, SMAD3 inhibition in combination with oxaliplatin effectively diminished tumor burden by impeding DNA repair. SMAD3 interacted directly with protein phosphatase 2A (PP2A), a key regulator of the DNA damage repair protein ataxia telangiectasia mutated (ATM). SMAD3 inhibition diminished ATM phosphorylation by enhancing the binding of PP2A to ATM, causing excessive levels of DNA damage.
Conclusions:
Our results identify SMAD3 as a promising therapeutic target for future combination strategies for the treatment of patients with EAC.
Insights
SMAD3 gene expression is higher in esophageal adenocarcinoma patients resistant to chemotherapy. Inhibiting SMAD3 with oxaliplatin reduced tumor burden by blocking DNA repair, identifying SMAD3 as a therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Transforming growth factor beta (TGFβ) signaling drives cancer progression and therapy resistance in many cancers, including esophageal adenocarcinoma (EAC).
- Understanding the molecular mechanisms of therapy resistance is crucial for developing effective treatment strategies for EAC.
Purpose of the Study:
- To investigate the role of SMAD family member 3 (SMAD3) in mediating resistance to oxaliplatin chemotherapy in esophageal adenocarcinoma.
- To identify potential therapeutic targets for overcoming oxaliplatin resistance in EAC.
Main Methods:
- Development of patient-derived organoid and xenograft models of EAC.
- Bioinformatics analysis and functional genetics to assess SMAD3 function.
- Investigated the interaction between SMAD3, protein phosphatase 2A (PP2A), and ataxia telangiectasia mutated (ATM) in DNA damage repair pathways.
Main Results:
- Elevated SMAD3 gene expression was observed in EAC patients who did not respond to chemotherapy compared to responders.
- SMAD3 inhibition, combined with oxaliplatin, significantly reduced tumor burden in patient-derived xenografts by impairing DNA repair.
- SMAD3 inhibition enhanced the binding of PP2A to ATM, leading to decreased ATM phosphorylation and excessive DNA damage accumulation.
Conclusions:
- SMAD3 plays a critical role in conferring resistance to oxaliplatin chemotherapy in esophageal adenocarcinoma.
- Targeting SMAD3 represents a promising therapeutic strategy for combination treatments to improve outcomes for EAC patients.
