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Targeting PKCι-PAK1 signaling pathways in EGFR and KRAS mutant adenocarcinoma and lung squamous cell carcinoma

Authors
  • Ito, Masaoki1, 2, 3
  • Codony-Servat, Carles1, 4
  • Codony-Servat, Jordi1
  • Lligé, David2
  • Chaib, Imane2
  • Sun, Xiaoyan5
  • Miao, Jing5
  • Sun, Rongwei5
  • Cai, Xueting5
  • Verlicchi, Alberto1, 6
  • Okada, Morihito3
  • Molina-Vila, Miguel Angel1
  • Karachaliou, Niki1
  • Cao, Peng5, 7, 8
  • Rosell, Rafael2, 9, 10
  • 1 Quiron-Dexeus University Institute, Pangaea Oncology, Laboratory of Molecular Biology, Barcelona, Spain , Barcelona (Spain)
  • 2 Laboratory of Cellular and Molecular Biology, Institute for Health Science Research Germans Trias i Pujol (IGTP), Badalona, Spain , Badalona (Spain)
  • 3 Hiroshima University, Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima, Japan , Hiroshima (Japan)
  • 4 IDIBELL/CReST/Translational Research Laboratori L’Hospitalet de Llobregat, Barcelona, Spain , Barcelona (Spain)
  • 5 Nanjing University of Chinese Medicine, Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing, China , Nanjing (China)
  • 6 Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy , Meldola (Italy)
  • 7 Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China , Nanjing (China)
  • 8 Nanjing Medical University, Collaborative Innovation Center for Cancer Medicine, Nanjing, China , Nanjing (China)
  • 9 Quiron-Dexeus University Institute, Institute of Oncology Rosell (IOR), Barcelona, Spain , Barcelona (Spain)
  • 10 Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol Campus Can Ruti (Edifici Muntanya), Ctra. de Can Ruti, Cami de les Escoles s/n, Badalona, Barcelona, 08916, Spain , Barcelona (Spain)
Type
Published Article
Journal
Cell Communication and Signaling
Publisher
BioMed Central
Publication Date
Oct 28, 2019
Volume
17
Issue
1
Identifiers
DOI: 10.1186/s12964-019-0446-z
Source
Springer Nature
License
Green

Abstract

Introductionp21-activated kinase 1 (PAK1) stimulates growth and metastasis in non-small cell lung cancer (NSCLC). Protein kinase C iota (PKCι) is an enzyme highly expressed in NSCLC, regulating PAK1 signaling. In the present study we explored whether the PKCι-PAK1 signaling pathway approach can be an efficient target in different types of NSCLC cell and mouse models.MethodsThe effect of IPA-3 (PAK1 inhibitor) plus auranofin (PKCι inhibitor) combination was evaluated by cell viability assay, colony formation and western blotting assay, using three types of NSCLC cell lines: EGFR or KRAS mutant adenocarcinoma and squamous cell carcinoma with PAK1 amplification. In addition, for clinical availability, screening for new PAK1 inhibitors was carried out and the compound OTSSP167 was evaluated in combination with auranofin in cell and mice models.ResultsThe combination of IPA-3 or OTSSP167 plus auranofin showed high synergism for inhibiting cell viability and colony formation in three cell lines. Mechanistic characterization revealed that this drug combination abrogated expression and activation of membrane receptors and downstream signaling proteins crucial in lung cancer: EGFR, MET, PAK1, PKCι, ERK1/2, AKT, YAP1 and mTOR. A nude mouse xenograft assay demonstrated that this drug combination strongly suppressed tumor volume compared with single drug treatment.ConclusionsCombination of IPA-3 or OTSSP167 and auranofin was highly synergistic in EGFR or KRAS mutant adenocarcinoma and squamous cell carcinoma cell lines and decreased tumor volume in mice models. It is of interest to further test the targeting of PKCι-PAK1 signaling pathways in EGFR mutant, KRAS mutant and squamous NSCLC patients.

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