American Association for Cancer Research
Browse
- No file added yet -

Supplementary Figure S7 from Targeting AKR1B10 by Drug Repurposing with Epalrestat Overcomes Chemoresistance in Non–Small Cell Lung Cancer Patient-Derived Tumor Organoids

Download (169.35 kB)
journal contribution
posted on 2024-09-03, 07:41 authored by Kanve N. Suvilesh, Yariswamy Manjunath, Yulia I. Nussbaum, Mohamed Gadelkarim, Murugesan Raju, Akhil Srivastava, Guangfu Li, Wesley C. Warren, Chi-Ren Shyu, Feng Gao, Matthew A. Ciorba, Jonathan B. Mitchem, Satyanarayana Rachagani, Jussuf T. Kaifi

Supplementary Figure S7. Dose titration of carboplatin and paclitaxel against PDTOs to determine the cytotoxicity.

Funding

U.S. Department of Veterans Affairs (VA)

Foundation for Barnes-Jewish Hospital (FBJH)

History

ARTICLE ABSTRACT

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. 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. 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. 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.

Usage metrics

    Clinical Cancer Research

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC