title: Inhibition of mitochondrial glutaminase activity reverses acquired erlotinib resistance in non-small cell lung cancer.
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.
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, P. R. China.
authors.forename: Caifeng
authors.initials: C
authors.lastname: Xie
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, P. R. China.
authors.forename: Jiangbo
authors.initials: J
authors.lastname: Jin
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, P. R. China.
authors.forename: Xujie
authors.initials: X
authors.lastname: Bao
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, P. R. China.
authors.forename: Wei-Hua
authors.initials: WH
authors.lastname: Zhan
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, P. R. China.
authors.forename: Tian-Yu
authors.initials: TY
authors.lastname: Han
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, P. R. China.
authors.forename: Mingxi
authors.initials: M
authors.lastname: Gan
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, P. R. China.
authors.forename: Chengfu
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, P. R. China.
authors.forename: Jianbin
authors.initials: J
authors.lastname: Wang
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D053119:Benzophenanthridines / Q000494:pharmacology*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology*; D005434:Flow Cytometry; D005972:Glutaminase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D013997:Time Factors
chemical_list: D053119:Benzophenanthridines; D047428:Protein Kinase Inhibitors; C000598981:compound 968; D000069347:Erlotinib Hydrochloride; D005972:Glutaminase
keywords: epidermal growth factor receptor; erlotinib; glutaminase inhibitor-968; non-small cell lung cancer