title: PAK1 Is a Novel Therapeutic Target in Tyrosine Kinase Inhibitor-Resistant Lung Adenocarcinoma Activated by the PI3K/AKT Signaling Regardless of EGFR Mutation.
abstract: OBJECTIVE
  EGFR mutation as a biomarker has documented that EGFR-mutant patients will derive clinical benefit from tyrosine kinase inhibitor (TKI) treatment. Unfortunately, most patients show TKI resistance and tumor recurrence after therapy. Therefore, we expected that an adjuvant biomarker other than EGFR mutation is needed for predicting TKI resistance.
  
  
  METHODS
  Molecular manipulations were performed to verify whether TKI resistance mediated by p21-activated kinase (PAK1) could be through increasing Mcl-1 protein stability via the PI3K/AKT/C/EBP-β/miR-145 cascade. Xenograft mouse models were used to confirm the mechanistic action of PAK1 on TKI resistance. Forty-six tumor tissues from patients with lung adenocarcinoma who received TKI therapy were collected to evaluate PAK1 and E-cadherin mRNA expressions by real-time PCR. The association of PAK1 and E-cadherin mRNA expressions with tumor response to TKI treatment and outcomes was evaluated.
  
  
  RESULTS
  We demonstrate that PAK1 confers TKI resistance in EGFR-mutant cells as well as in EGFR-wild-type cells. Mechanistically, the positive feedback loop of PAK1/PI3K/AKT/C/EBP-β/miR-145 cascades persistently activates the PI3K/AKT signaling pathway to protect Mcl-1 degradation by Fbw7, which results, in turn, in TKI resistance and cell invasion via epithelial-to-mesenchymal transition due to a decrease in E-cadherin expression. The mechanism underlying the cell model is further confirmed in xenograft tumors. Among patients, high-PAK1 or low-E-cadherin tumors more commonly exhibited an unfavorable response to TKI and poorer outcome compared with low-PAK1 or low-E-cadherin tumors.
  
  
  CONCLUSIONS
  The combination of TKI with AKT inhibitor might confer TKI sensitivity and in turn improve outcomes in patients with lung adenocarcinoma who harbored high PAK1 mRNA-expressing tumors. Clin Cancer Res; 22(21); 5370-82. ©2016 AACR.
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan, ROC.
authors.forename: De-Wei
authors.initials: DW
authors.lastname: Wu
authors.affiliation: Division of Chest Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan, ROC.
authors.forename: Tzu-Chin
authors.initials: TC
authors.lastname: Wu
authors.affiliation: Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan, ROC.
authors.forename: Chih-Yi
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan, ROC. hl@tmu.edu.tw.
authors.forename: Huei
authors.initials: H
authors.lastname: Lee
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D054462:p21-Activated Kinases / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D015820:Cadherins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D047428:Protein Kinase Inhibitors; D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; D066246:ErbB Receptors; C515903:PAK1 protein, human; D054462:p21-Activated Kinases