title: Effect of simvastatin on the resistance to EGFR tyrosine kinase inhibitors in a non-small cell lung cancer with the T790M mutation of EGFR.
abstract: Although non-small cell lung cancer (NSCLC) tumors with activating mutations in the epidermal growth factor receptor (EGFR) are highly responsive to EGFR tyrosine kinase inhibitors (TKIs) including gefitinib and erlotinib, development of acquired resistance is almost inevitable. Statins show antitumor activity, but it is unknown whether they can reverse EGFR-TKIs resistance in NSCLC with the T790M mutation of EGFR. This study investigated overcoming resistance to EGFR-TKI using simvastatin. We demonstrated that addition of simvastatin to gefitinib enhanced caspase-dependent apoptosis in T790M mutant NSCLC cells. Simvastatin also strongly inhibited AKT activation, leading to suppression of β-catenin activity and the expression of its targets, survivin and cyclin D1. Both insulin treatment and AKT overexpression markedly increased p-β-catenin and survivin levels, even in the presence of gefitinib and simvastatin. However, inhibition of AKT by siRNA or LY294002 treatment decreased p-β-catenin and survivin levels. To determine the role of survivin in simvastatin-induced apoptosis of gefitinib-resistant NSCLC, we showed that the proportion of apoptotic cells following treatment with survivin siRNA and the gefitinib-simvastatin combination was greater than the theoretical additive effects, whereas survivin up-regulation could confer protection against gefitinib and simvastatin-induced apoptosis. Similar results were obtained in erlotinib and simvastatin-treated HCC827/ER cells. These findings suggest that survivin is a key molecule that renders T790M mutant NSCLC cells resistant to apoptosis induced by EGFR-TKIs and simvastatin. Overall, these data indicate that simvastatin may overcome EGFR-TKI resistance in T790M mutant NSCLCs via an AKT/β-catenin signaling-dependent down-regulation of survivin and apoptosis induction.
authors.affiliation: Department of Internal Medicine, Institute of Wonkwang Medical Science, Wonkwang University, School of Medicine, 344-2 shinyong-dong, Iksan, Jeonbuk 570-749, Republic of Korea.
authors.forename: Ki-Eun
authors.initials: KE
authors.lastname: Hwang
authors.affiliation: Department of Internal Medicine, Institute of Wonkwang Medical Science, Wonkwang University, School of Medicine, 344-2 shinyong-dong, Iksan, Jeonbuk 570-749, Republic of Korea.
authors.forename: Su-Jin
authors.initials: SJ
authors.lastname: Kwon
authors.affiliation: Department of Internal Medicine, Institute of Wonkwang Medical Science, Wonkwang University, School of Medicine, 344-2 shinyong-dong, Iksan, Jeonbuk 570-749, Republic of Korea.
authors.forename: Young-Suk
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Department of Laboratory Medicine, Wonkwang University, School of Medicine, Iksan, Republic of Korea.
authors.forename: Do-Sim
authors.initials: DS
authors.lastname: Park
authors.affiliation: Department of Obstetrics & Gynecology, Wonkwang University, School of Medicine, Iksan, Republic of Korea.
authors.forename: Byoung-Ryun
authors.initials: BR
authors.lastname: Kim
authors.affiliation: Department of Radiology, Wonkwang University, School of Medicine, Iksan, Republic of Korea.
authors.forename: Kwon-Ha
authors.initials: KH
authors.lastname: Yoon
authors.affiliation: Department of Internal Medicine, Institute of Wonkwang Medical Science, Wonkwang University, School of Medicine, 344-2 shinyong-dong, Iksan, Jeonbuk 570-749, Republic of Korea.
authors.forename: Eun-Taik
authors.initials: ET
authors.lastname: Jeong
authors.affiliation: Department of Internal Medicine, Institute of Wonkwang Medical Science, Wonkwang University, School of Medicine, 344-2 shinyong-dong, Iksan, Jeonbuk 570-749, Republic of Korea. Electronic address: kshryj@wonkwang.ac.kr.
authors.forename: Hak-Ryul
authors.initials: HR
authors.lastname: Kim
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D051177:Catenins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D000077156:Gefitinib; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D019821:Simvastatin / Q000494:pharmacology*; D000077022:Survivin
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D051177:Catenins; D051034:Inhibitor of Apoptosis Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077022:Survivin; D019821:Simvastatin; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: EGFR tyrosine kinase inhibitors; Lung cancer; Resistance; Simvastatin