title: TPCA-1 is a direct dual inhibitor of STAT3 and NF-κB and regresses mutant EGFR-associated human non-small cell lung cancers.
abstract: Epidermal growth factor receptor (EGFR) is a clinical therapeutic target to treat a subset of non-small cell lung cancer (NSCLC) harboring EGFR mutants. However, some patients with a similar kind of EGFR mutation show intrinsic resistance to tyrosine kinase inhibitors (TKI). It indicates that other key molecules are involved in the survival of these cancer cells. We showed here that 2-[(aminocarbonyl)amino]-5 -(4-fluorophenyl)-3- thiophenecarboxamide (TPCA-1), a previously reported inhibitor of IκB kinases (IKK), blocked STAT3 recruitment to upstream kinases by docking into SH2 domain of STAT3 and attenuated STAT3 activity induced by cytokines and cytoplasmic tyrosine kinases. TPCA-1 is an effective inhibitor of STAT3 phosphorylation, DNA binding, and transactivation in vivo. It selectively repressed proliferation of NSCLC cells with constitutive STAT3 activation. In addition, using pharmacologic and genetic approaches, we found that both NF-κB and STAT3 could regulate the transcripts of interleukin (IL)-6 and COX-2 in NSCLC harboring EGFR mutations. Moreover, gefitinib treatment only did not efficiently suppress NF-κB and STAT3 activity. In contrast, we found that treatment with TKIs increased phosho-STAT3 level in target cells. Inhibiting EGFR, STAT3, and NF-κB by combination of TKIs with TPCA-1 showed increased sensitivity and enhanced apoptosis induced by gefitinib. Collectively, in this work, we identified TPCA-1 as a direct dual inhibitor for both IKKs and STAT3, whereas treatment targeting EGFR only could not sufficiently repress NF-κB and STAT3 pathways for lung cancers harboring mutant EGFR. Therefore, synergistic treatment of TPCA-1 with TKIs has potential to be a more effective strategy for cancers.
authors.affiliation: Corresponding Author: Jinbo Yang, School of Life Science, Lanzhou University, Lanzhou, Gansu 730000, China. yangjb@lzu.edu.cn.
authors.forename: Jing
authors.initials: J
authors.lastname: Nan
authors.forename: Yuping
authors.initials: Y
authors.lastname: Du
authors.forename: Xing
authors.initials: X
authors.lastname: Chen
authors.forename: Qifeng
authors.initials: Q
authors.lastname: Bai
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Wang
authors.forename: Xinxin
authors.initials: X
authors.lastname: Zhang
authors.forename: Ning
authors.initials: N
authors.lastname: Zhu
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Jianwen
authors.initials: J
authors.lastname: Hou
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.forename: Jinbo
authors.initials: J
authors.lastname: Yang
mesh_terms: D000577:Amides / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004357:Drug Synergism; D066246:ErbB Receptors / Q000235:genetics*; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D009154:Mutation; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics*; D011799:Quinazolines / Q000008:administration & dosage; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D013876:Thiophenes / Q000008:administration & dosage
chemical_list: D000577:Amides; D020672:I-kappa B Proteins; D016328:NF-kappa B; D011799:Quinazolines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013876:Thiophenes; C499326:2-((aminocarbonyl)amino)-5-(4-fluorophenyl)-3-thiophenecarboxamide; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib