Abstract 6071: Role of AKR1B10 inhibition in modulating NSCLC therapy responses

Abstract Background: Non-small cell lung cancer (NSCLC) has devastating impacts in patients undergoing surgical resection with a poor overall survival rate of 26%. Standard-of-care NSCLC chemoimmunotherapy is often ineffective due to drug resistance, resulting in cancer recurrence, a critical clinical gap that needs be addressed immediately. Our previous study outlined the clinical utility of NSCLC patient-derived tumor organoids to identify drug repurposing target (aldoketoreductase family 1 member B10 (AKR1B10)) to overcome resistance towards standard-of-care platinum-based doublet chemotherapy. In this study, we will provide insights into the role of AKR1B10 in tumor progression and therapy responses in immunocompetent mouse models using multiple approaches of regulating AKR1B10 expression. Experimental Design: Tamoxifen-inducible lung-specific AKR1B10 knockout (AKO) mouse was developed to evaluate the effect of AKR1B10 on initiation, progression, metastatic potential and therapy responses. Knockdown of AKR1B10 was confirmed by western blotting and immunohistochemistry (IHC). Alternatively, lentiviral mediated AKR1B10 knockout was achieved in KrasG12DP53mut (KP) lung cancer cell lines. Parental and AKR1B10 knockout KP cell lines were injected into C57BL/6 mice to evaluate tumor progression and therapy responses. In both experimental models, phenotype and frequency of infiltrating immune cells in lung (tumor) tissues was determined by flow cytometry. Results: Lungs from AKO mice were significantly smaller (reduced lung weight/body weight) compared to littermate controls. Western blotting and IHC revealed low AKR1B10 expression compared to littermate controls. Lentiviral mediated knockdown of AKR1B10 in mouse KP cells resulted in significantly low AKR1B10 expression (Western blotting) compared to parental cells. Further, AKR1B10 knockdown modulated the tumorigenic potential evident by the reduced tumor burden and had positive impact on chemotherapy outcome. These findings were supported by the therapeutic potential of repurposed AKR1B10 inhibitor epalrestat to overcome chemotherapy resistance. Gross tissue and histological findings were supported by altered frequency of infiltrating immune cells in lung tissues and draining lymph nodes from AKO mice compared to littermate controls. Conclusions: AKR1B10 plays a critical role in NSCLC progression and immune cell infiltration in tumor microenvironment. Modulation of AKR1B10 expression using adjuvant small molecular inhibitor and genomic modulation methods indicated the role of AKR1B10 in NSCLC therapy responses. Epalrestat, a repurposed AKR1B10 inhibitory drug has the potential to advance to clinical trials in patients with drug-resistant NSCLC due to favorable toxicity, brain-penetrability, pharmacological profile, and bioavailability. Overall, the study aims at improving the therapy outcomes and reducing the mortality in NSCLC patients. Citation Format: Yariswamy Manjunath, Suvilesh Kanve Nagaraj, Sudheer Kanumuri, Satyanarayana Rachagani, Emma Teixeiro Pernas, Jussuf T. Kaifi. Role of AKR1B10 inhibition in modulating NSCLC therapy responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6071.