title: 244-MPT overcomes gefitinib resistance in non-small cell lung cancer cells.
abstract: The epidermal growth factor receptor (EGFR) is known to play a critical role in non-small cell lung cancer(NSCLC). Several EGFR tyrosine kinase inhibitors(TKIs), such as gefitinib, have been used as effective clinical therapies for patients with NSCLC. Unfortunately, acquired resistance to gefitinib commonly occurs after 6-12 months of treatment. The resistance is associated with the appearance of the L858R/T790M double mutation of the EGFR. In our present study, we discovered a compound,referred to as 244-MPT, which could suppress either gefitinib-sensitive or -resistant lung cancer cell growth and colony formation, and also suppressed the kinase activity of both wildtype and double mutant (L858R/T790M) EGFR. The underlying mechanism reveals that 244-MPT could interact with either the wildtype or double-mutant EGFR in an ATP-competitive manner and inhibit activity. Treatment with 244-MPT could substantially reduce the phosphorylation of EGFR and its downstream signaling pathways, including Akt and ERK1/2 in gefitinib-sensitive and -resistant cell lines. It was equally effective in suppressing EGFR phosphorylation and downstream signaling in NL20 cells transfected with wildtype, single-mutant (L858R) or mutant (L858R/T790M) EGFR. 244-MPT could also induce apoptosis in a gefitinib-resistant cell line and strongly suppress gefitinib-resistant NSCLC tumor growth in a xenograft mouse model. In addition, 244-MPT could effectively reduce the size of tumors in a gefitinib-resistant NSCLC patient-derived xenograft (PDX) SCID mouse model. Overall, 244-MPT could overcome gefitinib-resistance by directly targeting the EGFR.
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.|Pathophysiology Department, Basic Medical College, Zhengzhou University, Henan, China.|The First Affiliated Hospital of Zhengzhou University, Henan, China.|The China-US (Henan) Hormel Cancer Institute, Henan, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.|Pathophysiology Department, Basic Medical College, Zhengzhou University, Henan, China.|The China-US (Henan) Hormel Cancer Institute, Henan, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Yao
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.|The First Affiliated Hospital of Zhengzhou University, Henan, China.|The China-US (Henan) Hormel Cancer Institute, Henan, China.
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Shi
authors.affiliation: Pathophysiology Department, Basic Medical College, Zhengzhou University, Henan, China.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.|Pathophysiology Department, Basic Medical College, Zhengzhou University, Henan, China.|The China-US (Henan) Hormel Cancer Institute, Henan, China.
authors.forename: Kangdong
authors.initials: K
authors.lastname: Liu
authors.affiliation: The First Affiliated Hospital of Zhengzhou University, Henan, China.
authors.forename: Song
authors.initials: S
authors.lastname: Zhao
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: Hanyong
authors.initials: H
authors.lastname: Chen
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: Kanamata
authors.initials: K
authors.lastname: Reddy
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.|Pathophysiology Department, Basic Medical College, Zhengzhou University, Henan, China.|The Affiliated Cancer Hospital of Zhengzhou University, Henan, China.
authors.forename: Chengjuan
authors.initials: C
authors.lastname: Zhang
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Chang
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: Joohyun
authors.initials: J
authors.lastname: Ryu
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.affiliation: Pathophysiology Department, Basic Medical College, Zhengzhou University, Henan, China.
authors.forename: Ziming
authors.initials: Z
authors.lastname: Dong
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.|The China-US (Henan) Hormel Cancer Institute, Henan, China.
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D000077156:Gefitinib; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008819:Mice, Nude; D016513:Mice, SCID; D056004:Molecular Dynamics Simulation; D009154:Mutation; D010636:Phenols / Q000494:pharmacology*; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011799:Quinazolines / Q000378:metabolism / Q000494:pharmacology*; D015398:Signal Transduction; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C000611950:2-(4-(4-methoxyphenoxy)-1H-pyrazol-3-yl)-5-(p-tolylmethoxy)phenol; D000970:Antineoplastic Agents; D010636:Phenols; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011799:Quinazolines; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D000077156:Gefitinib
keywords: epidermal growth factor receptor (EGFR); gefitinib resistance; non-small cell lung cancer (NSCLC)