title: Bidirectional signaling between TM4SF5 and IGF1R promotes resistance to EGFR kinase inhibitors.
abstract: OBJECTIVE
  The membrane glycoprotein TM4SF5 (transmembrane 4 L6 family member 5), which is similar to the tetraspanins, is highly expressed in different cancers and causes epithelial-mesenchymal transition (EMT). TM4SF5 interacts with other membrane proteins during its pro-tumorigenic roles, presumably at tetraspanin-enriched microdomains (TEMs/TERMs). Here, we explored TM4SF5-mediated resistance against the clinically important EGFR kinase inhibitors, with regards to cooperation with other membrane proteins, particularly the insulin-like growth factor 1 receptor (IGF1R).
  
  
  METHODS
  Using cancer cells including NSCLC with TM4SF5 overexpression or IGF1R suppression in either normal 2 dimensional (2D), 3D aqueous spheroids, or 3D collagen I gels systems, the sensitivity to tyrosine kinase inhibitors (TKIs) were evaluated.
  
  
  CONCLUSIONS
  We found that TM4SF5 and IGF1R transcriptionally modulated one another, with each protein promoting the expressions of the other. Expression of TM4SF5 in gefitinib-sensitive HCC827 cells caused resistance to erlotinib and gefitinib, but not to sorafenib [a platelet derived growth factor receptor (PDGFR) inhibitor]; whereas suppression of IGF1R from gefitinib-resistant NCI-H1299 cells caused enhanced sensitization to the inhibitors. Expression of TM4SF5 and IGF1R in the drug-sensitive cells promoted signaling activities of extracellular signal-regulated kinases (ERKs), protein kinase B (Akt), and S6 kinase (S6K), and resulted in a higher residual EGFR activity, even after EGFR kinase inhibitor treatment. Complex formation between TM4SF5 and IGF1R was observed, and also included EGFR, dependent on TM4SF5 expression. The TM4SF5-mediated drug resistance was further confirmed in an aqueous 3D spheroid system or upon being embedded in 3D extracellular matrix (ECM)-surrounded gel systems. Collectively, these data suggest that anti-TM4SF5 reagents may be combined with the EGFR kinase inhibitors to enhance the efficacy of chemotherapies against NSCLC.
authors.affiliation: Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Jungeun
authors.initials: J
authors.lastname: Choi
authors.affiliation: Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Minkyung
authors.initials: M
authors.lastname: Kang
authors.affiliation: Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Seo Hee
authors.initials: SH
authors.lastname: Nam
authors.affiliation: Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Gyu-Ho
authors.initials: GH
authors.lastname: Lee
authors.affiliation: Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Hye-Jin
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Jihye
authors.initials: J
authors.lastname: Ryu
authors.affiliation: Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Jin Gyu
authors.initials: JG
authors.lastname: Cheong
authors.affiliation: Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Jae Woo
authors.initials: JW
authors.lastname: Jung
authors.affiliation: Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Tai Young
authors.initials: TY
authors.lastname: Kim
authors.affiliation: Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Ho-Young
authors.initials: HY
authors.lastname: Lee
authors.affiliation: Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul 151-742, Republic of Korea; Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea. Electronic address: jwl@snu.ac.kr.
authors.forename: Jung Weon
authors.initials: JW
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology*; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D018874:Spheroids, Cellular
chemical_list: D000970:Antineoplastic Agents; C000597236:IGF1R protein, human; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D017451:Receptors, Somatomedin; C111029:TM4SF5 protein, human; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1; D000077156:Gefitinib
keywords: Epithelial–mesenchymal transition; Gefitinib resistance; IGF1R; Non-small-cell lung carcinoma; TM4SF5