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Targeting AKR1B10 by Drug Repurposing with Epalrestat Overcomes Chemoresistance in Non-Small Cell Lung Cancer
Kanve N Suvilesh1,2, Yariswamy Manjunath1,2, Yulia I Nussbaum3
1Department of Surgery, Ellis Fischel Cancer Center, Roy Blunt NextGen Precision Health Institute, University of Missouri, Columbia, Missouri.
Purpose:
Systemic treatments given to patients with non-small cell lung cancer (NSCLC) are often ineffective due to drug resistance. In the present study, we investigated patient-derived tumor organoids (PDTO) and matched tumor tissues from surgically treated patients with NSCLC to identify drug repurposing targets to overcome resistance toward standard-of-care platinum-based doublet chemotherapy.
Experimental Design:
PDTOs were established from 10 prospectively enrolled patients with non-metastatic NSCLC from resected tumors. PDTOs were compared with matched tumor tissues by histopathology/immunohistochemistry, whole exome sequencing, and transcriptome sequencing. PDTO growths and drug responses were determined by measuring 3D tumoroid volumes, cell viability, and proliferation/apoptosis. Differential gene expression analysis identified drug-repurposing targets. Validations were performed with internal/external data sets of patients with NSCLC. NSCLC cell lines were used for aldo-keto reductase 1B10 (AKR1B10) knockdown studies and xenograft models to determine the intratumoral bioavailability of epalrestat.
Results:
PDTOs retained histomorphology and pathological biomarker expression, mutational/transcriptomic signatures, and cellular heterogeneity of the matched tumor tissues. Five (50%) PDTOs were chemoresistant toward carboplatin/paclitaxel. Chemoresistant PDTOs and matched tumor tissues demonstrated overexpression of AKR1B10. Epalrestat, an orally available AKR1B10 inhibitor in clinical use for diabetic polyneuropathy, was repurposed to overcome chemoresistance of PDTOs. In vivo efficacy of epalrestat to overcome drug resistance corresponded to intratumoral epalrestat levels.
Conclusions:
PDTOs are efficient preclinical models recapitulating the tumor characteristics and are suitable for drug testing. AKR1B10 can be targeted by repurposing epalrestat to overcome chemoresistance in NSCLC. Epalrestat has the potential to advance to clinical trials in patients with drug-resistant NSCLC due to favorable toxicity, pharmacological profile, and bioavailability.
Insights
Patient-derived tumor organoids effectively model non-small cell lung cancer (NSCLC) and reveal AKR1B10 as a target. Repurposing epalrestat may overcome chemoresistance in NSCLC patients.
Area of Science:
- Oncology
- Translational Research
- Drug Discovery
Background:
- Systemic treatments for non-small cell lung cancer (NSCLC) often fail due to acquired drug resistance.
- Developing effective strategies to overcome chemoresistance is crucial for improving patient outcomes in NSCLC.
Purpose of the Study:
- To investigate patient-derived tumor organoids (PDTOs) and matched tumor tissues from NSCLC patients to identify drug repurposing targets.
- To overcome resistance to standard-of-care platinum-based doublet chemotherapy in non-small cell lung cancer.
Main Methods:
- Established and characterized PDTOs from 10 NSCLC patients, comparing them with matched tumor tissues using histopathology, immunohistochemistry, and multi-omics sequencing.
- Assessed PDTO growth and drug responses via 3D tumoroid volume, cell viability, proliferation, and apoptosis assays.
- Identified drug-repurposing targets through differential gene expression analysis and validated findings using cell lines, xenograft models, and patient datasets.
Main Results:
- PDTOs accurately recapitulated the histomorphology, biomarker expression, mutational/transcriptomic signatures, and cellular heterogeneity of the original tumors.
- Fifty percent of PDTOs exhibited chemoresistance to carboplatin/paclitaxel, correlating with overexpression of aldo-keto reductase 1B10 (AKR1B10) in both PDTOs and matched tissues.
- Repurposed epalrestat, an AKR1B10 inhibitor, effectively overcame chemoresistance in PDTOs, with in vivo efficacy linked to intratumoral drug levels.
Conclusions:
- PDTOs serve as efficient preclinical models for recapitulating tumor characteristics and facilitating drug testing in NSCLC.
- Targeting AKR1B10 by repurposing epalrestat shows promise for overcoming chemoresistance in non-small cell lung cancer.
- Epalrestat's favorable toxicity, pharmacological profile, and bioavailability suggest its potential for clinical trials in drug-resistant NSCLC patients.
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