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New Mechanism to Overcome Acquired Resistance to EGFR-Targeted Therapy in Lung Cancer

October 18, 2021      Author:

Lung cancer is the leading cause of cancer death in China and around the world. EGFR TKI-targeted therapy, highly effective to lung cancer, has been regarded as a model treatment approach of precision medicine. However, acquired resistance is almost inevitable after the initial treatment, which greatly limits the clinical efficacy, remaining a serious challenge for treating the disease.

 

On October 7, Zhu Liang’s research team from the Department of Pharmacology and Chemical Biology, College of Basic Medical Sciences, SJTU, published an article in Science Translational Medicine, titled “Targeting AKR1B1 Inhibits Glutathione de Novo Synthesis to Overcome Acquired Resistance to EGFR-targeted Therapy in Lung Cancer”. In this article, the team revealed a new mechanism of EGFR TKI drug resistance in lung cancer and suggested a new therapeutic strategy to overcome such acquired resistance.

 

This study identifies metabolic mechanism for resistance to EGFR TKIs in lung cancer and suggests the existence of metabolic reprogramming drivers of targeted drug resistance in solid tumors. The AKR key node identified is a new mechanism which is common to multiple generations of EGFR-TKI targeted agents, and the pharmacological interventions have been shown to prevent and overcome drug resistance in preclinical trials, including the third-generation inhibitor osimertinib. The study was published with an editorial note, suggesting the implications of the study for treatment strategies to overcome EGFR-targeted drug resistance.

The co-first authors of this paper are doctoral student Zhang Keren, graduate Zhang Yufei, graduate Lei Huimin, and Dr. Tang Yabin. Prof. Zhu Liang, Prof. Chen Hongzhuan, and researcher Shen Ying are the co-corresponding authors. The research was funded by the National Natural Science Foundation of China and Shanghai Municipal Science Commission. It was also supported by Shanghai Collaborative Innovation Center of Translational Medicine. The corresponding medicine usage findings are under the process of patent application (No. 202010498449.0)

 

Author: School of Medicine, SJTU

 Source: WeChat Account of School of Medicine, SJTU

Translated by Zhang Yue

 

 

 

ABSTRACT:

Acquired resistance represents a bottleneck to molecularly targeted therapies such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment in lung cancer. A deeper understanding of resistance mechanisms can provide insights into this phenomenon and help to develop additional therapeutic strategies to overcome or delay resistance. Here, we identified a pharmacologically targetable metabolic mechanism that drives resistance to EGFR TKIs in lung cancer cell lines and patient-derived xenograft mice. We demonstrated that aldo-keto reductase family 1 member B1 (AKR1B1) interacts with and activates signal transducer and activator of transcription 3 (STAT3) to up-regulate the cystine transporter solute carrier family 7 member 11 (SLC7A11). This leads to enhanced cystine uptake and flux to glutathione de novo synthesis, reactive oxygen species (ROS) scavenging, protection from cell death, and EGFR TKI drug resistance in lung cancer cell lines and xenograft mouse models. Suppression of AKR1B1 with selective inhibitors, including the clinically approved antidiabetic drug epalrestat, restored the sensitivity of resistant cell lines to EGFR TKIs and delayed resistance in lung cancer patient-derived xenograft mice. Our findings suggest a metabolic mechanism for resistance to a molecularly targeted therapy and provide a potential therapeutic target for overcoming resistance to EGFR TKIs, including the third-generation inhibitor osimertinib.