Inhibition of mitochondrial glutaminase activity reverses acquired erlotinib resistance in non-small cell lung cancer

// Caifeng Xie 1 , Jiangbo Jin 1 , Xujie Bao 1 , Wei-Hua Zhan 1 , Tian-Yu Han 1 , Mingxi Gan 1 , Chengfu Zhang 1 , Jianbin Wang 1 1 Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, P. R. China Correspondence to: Jianbin Wang, e-mail: jianbinwang1@gmail.com Keywords: non-small cell lung cancer, erlotinib, glutaminase inhibitor-968, epidermal growth factor receptor Received: April 12, 2015 Accepted: October 29, 2015 Published: November 13, 2015 ABSTRACT The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib has been approved based on the clinical benefit in non-small cell lung cancer (NSCLC) patients over the past decade. Unfortunately, cancer cells become resistant to this agent via various mechanisms, and this limits the improvement in patient outcomes. Thus, it is urgent to develop novel agents to overcome erlotinib resistance. Here, we propose a novel strategy to overcome acquired erlotinib resistance in NSCLC by inhibiting glutaminase activity. Compound 968, an inhibitor of the glutaminase C (GAC), when combined with erlotinib potently inhibited the cell proliferation of erlotinib-resistant NSCLC cells HCC827ER and NCI-H1975. The combination of compound 968 and erlotinib not only decreased GAC and EGFR protein expression but also inhibited GAC activity in HCC827ER cells. The growth of erlotinib-resistant cells was glutamine-dependent as proved by GAC gene knocked down and rescue experiment. More importantly, compound 968 combined with erlotinib down-regulated the glutamine and glycolysis metabolism in erlotinib-resistant cells. Taken together, our study provides a valuable approach to overcome acquired erlotinib resistance by blocking glutamine metabolism and suggests that combination of EGFR-TKI and GAC inhibitor maybe a potential treatment strategy for acquired erlotinib-resistant NSCLC.