title: Combined therapeutic potential of nuclear receptors with receptor tyrosine kinase inhibitors in lung cancer.
abstract: Cancer heterogeneity is a big hurdle in achieving complete cancer treatment, which has led to the emergence of combinational therapy. In this study, we investigated the potential use of nuclear receptor (NR) ligands for combinational therapy with other anti-cancer drugs. We first profiled all 48 NRs and 48 biological anti-cancer targets in four pairs of lung cell lines, where each pair was obtained from the same patient. Two sets of cell lines were normal and the corresponding tumor cell lines while the other two sets consisted of primary versus metastatic tumor cell lines. Analysis of the expression profile revealed 11 NRs and 15 cancer targets from the two pairs of normal versus tumor cell lines, and 9 NRs and 9 cancer targets from the primary versus metastatic tumor cell lines had distinct expression patterns in each category. Finally, the evaluation of nuclear receptor ligand T0901317 for liver X receptor (LXR) demonstrated its combined therapeutic potential with tyrosine kinase inhibitors. The combined treatment of cMET inhibitor PHA665752 or EGFR inhibitor gefitinib with T0901317 showed additive growth inhibition in both H2073 and H1993 cells. Mechanistically, the combined treatment suppressed cell cycle progression by inhibiting cyclinD1 and cyclinB expression. Taken together, this study provides insight into the potential use of NR ligands in combined therapeutics with other biological anti-cancer drugs.
authors.affiliation: Department of Biochemistry, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701, Republic of Korea; Institute of Lifestyle Medicine, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701, Republic of Korea; Nuclear Receptor Research Consortium, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701, Republic of Korea.
authors.forename: Peninah M
authors.initials: PM
authors.lastname: Wairagu
authors.affiliation: Department of Pathology, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701, Republic of Korea.
authors.forename: Kwang Hwa
authors.initials: KH
authors.lastname: Park
authors.affiliation: Department of Biochemistry, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701, Republic of Korea; Institute of Lifestyle Medicine, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701, Republic of Korea; Nuclear Receptor Research Consortium, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701, Republic of Korea.
authors.forename: Jihye
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701, Republic of Korea.
authors.forename: Jong-Whan
authors.initials: JW
authors.lastname: Choi
authors.affiliation: Department of Biochemistry, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701, Republic of Korea.
authors.forename: Hyun-Won
authors.initials: HW
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701, Republic of Korea.
authors.forename: Byung-Il
authors.initials: BI
authors.lastname: Yeh
authors.affiliation: Department of Pathology, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701, Republic of Korea.
authors.forename: Soon-Hee
authors.initials: SH
authors.lastname: Jung
authors.affiliation: Department of Internal Medicine, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701, Republic of Korea.
authors.forename: Suk-Joong
authors.initials: SJ
authors.lastname: Yong
authors.affiliation: Department of Biochemistry, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701, Republic of Korea; Institute of Lifestyle Medicine, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701, Republic of Korea; Nuclear Receptor Research Consortium, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701, Republic of Korea. Electronic address: yjeong@yonsei.ac.kr.
authors.forename: Yangsik
authors.initials: Y
authors.lastname: Jeong
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D045744:Cell Line, Tumor; D019926:Cyclin B / Q000037:antagonists & inhibitors; D019938:Cyclin D1 / Q000037:antagonists & inhibitors; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000077156:Gefitinib; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000627:therapeutic use; D007211:Indoles / Q000627:therapeutic use; D000071518:Liver X Receptors; D008175:Lung Neoplasms / Q000188:drug therapy*; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D013449:Sulfonamides / Q000627:therapeutic use; D013450:Sulfones / Q000627:therapeutic use; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D000970:Antineoplastic Agents; D019926:Cyclin B; D019938:Cyclin D1; D066246:ErbB Receptors; D000077156:Gefitinib; D006845:Hydrocarbons, Fluorinated; D007211:Indoles; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; D013450:Sulfones; C480541:5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
keywords: Combinational therapy; LXR; Lung cancer; PPARγ; Tyrosine kinase inhibitors