Amino Acid Facilitates Drug Resistance In Lung Cancer

Despite the remarkable success of molecular targeted therapy in recent years, the rapid increase of drug resistance is a major obstacle to effective treatment of lung cancer. How do lung cancer cells adapt to targeted therapy? What is the molecular basis of such adaptive behavior? Can this adaptive response be memorized by cancer cells? If so, is it heritable? The answers to these questions will provide a deeper understanding of the evolutionary process of drug resistance during molecular targeted therapy.

Mediators of resistance

Recently, metabolic alterations have been shown to play a role in the sensitivity of cancer cells to widely-used first-line chemotherapeutics. This suggests that metabolic pathways are important mediators of resistance toward anticancer agents. In this review, we highlight the metabolic alterations associate with resistance toward different anticancer agents and discuss how metabolism may be exploit to overcome drug resistance to classical chemotherapy.

In a study published online in Cell Reports, research teams led by Dr. Ji Hongbin at the Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences, Dr. Zhou Caicun at the Shanghai Pulmonary Hospital, Tongji University School of Medicine, and Dr. Li Cheng at the School of Life Sciences, Peking University, reveal the important role of epigenetic regulation-mediate metabolic reprogramming in lung cancer’s capacity to resist molecular target therapy.

The researchers found that low-dose target drug pretreatment allow epidermal growth factor receptor (EGFR)-mutant lung cancer cells to adapt to subsequent high-dose drug treatment, thus exhibiting a transient drug-tolerant state. They also found that continuous stimulation with low-dose drugs reinforce this adaptive response; also eventually promoted the development of drug resistance.

Lung cancer types

Such adaptive behavior occurs not only in EGFR-mutant lung cancer, but also in ALK-rearrange lung cancer, thus indicating this phenomenon is not restrict to one lung cancer type. In addition, the researchers reveal the molecular basis of this adaptive response, which involves epigenetic regulation-mediate metabolic reprogramming.

During the adaptation of lung cancer cells to drug therapy; so the level of intracellular histone H3K9 methylation is reduce, thus up-regulating the branched-chain amino acid aminotransferase 1 (BCAT1). In this process, more glutathione is generate by BCAT1, thereby effectively eliminating detrimental oxidative stress; so cause by target therapy and eventually causing drug resistance.

Not surprisingly, correlation analyses of clinical data show; so that high expression of BCAT1 in tumors is associate with an unfavorable therapeutic response; hence to drug treatment and predicts poor patient prognosis. However, using preclinical mouse models, the researchers demonstrate; so that the combination of target therapies with reactive oxygen species (ROS)-inducing drugs can effectively overcome lung cancer drug resistance, suggesting a potential therapeutic strategy for dealing with such drug resistance