Abstract 5958: Exploring AKR1C3 as a therapeutic target to overcome erlotinib resistance in lung adenocarcinoma
Authors: Cho William C. , Li Kwan P. , Wong Chi F. , Fung King Y. , Chow James C. , Cheung Ka M. , Chan Jeffrey C. , Lau Eunice Y. 
Published: March 2024

Introduction: Erlotinib has demonstrated promising efficacy in lung adenocarcinoma (LUAD) patients with epidermal growth factor receptor mutation. However, the development of resistance to erlotinib poses a significant challenge in achieving long-lasting treatment responses. Aldo-keto reductase family 1 member C3 (AKR1C3) is associated with tumor progression, drug resistance, and unfavorable prognosis. This study aims to assess the potential of AKR1C3 as a therapeutic target for overcoming erlotinib resistance in LUAD.

Methods: AKR1C3 expression was assessed in paired tumor tissues from 100 LUAD patients using reverse transcription quantitative polymerase chain reaction. Both in vitro and in vivo experiments were categorized into four treatment groups: a saline control (CTR), erlotinib (ER), an AKR1C3 inhibitor 3-(4-trifluoromethyl)phenylamino)benzoic acid (BA), and the combination of erlotinib with the AKR1C3 inhibitor (COM). An erlotinib-resistant cell line was established from the LUAD cell line HCC4006. The MTS assay was used to evaluate cell proliferation and viability. The combined effect of erlotinib and the AKR1C3 inhibitor was assessed using Synergyfinder and CompuSyn calculation software. Both cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models of erlotinib resistance to LUAD were established in NSG mice. The mice received daily oral gavage administration of the drugs for 31 days, while tumor volume was monitored biweekly.

Results: AKR1C3 expression was significantly upregulated by more than three-fold in LUAD tumor samples compared to normal counterparts (p &lt; 0.0001). After 24 hours of treatment in erlotinib-resistant cells, the ER and BA groups exhibited inhibition rates of 7% and 9%, respectively, while the COM group demonstrated a substantially higher inhibition rate of 45%. Synergyfinder and CompuSyn analysis revealed a synergy score of 12 and a combination index of 0.5 for the COM group, indicating a robust synergistic effect between the two drugs. In the CDX model, the COM group exhibited a tumor volume reduction of 25% in erlotinib-resistant cells and 64% in parental cells compared to the CTR group. In the PDX model, the COM group displayed a significant reduction of 50.4% in tumor volume compared to the CTR group. There was no significant difference in the weight of body and internal organs among the four treatment groups in both xenograft models.

Conclusions: AKR1C3 overexpression was observed in the tumor tissues of LUAD patients. The combination of erlotinib and AKR1C3 inhibitor showed promising efficacy in overcoming erlotinib resistance in both in vitro and in vivo experiments. These findings highlight AKR1C3 as a potential therapeutic target for managing erlotinib resistance in LUAD patients. Targeting AKR1C3 represents a novel approach to overcome resistance and enhance treatment outcomes in LUAD patients undergoing erlotinib therapy.

Citation Format: William C. Cho, Kwan P. Li, Chi F. Wong, King Y. Fung, James C. Chow, Ka M. Cheung, Jeffrey C. Chan, Eunice Y. Lau. Exploring AKR1C3 as a therapeutic target to overcome erlotinib resistance in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5958.