63P - Molecular bases for combinatorial treatment strategies in KRAS mutant (KRASm) lung adenocarcinoma (LAC)

Date 15 April 2016
Event European Lung Cancer Conference 2016 (ELCC) 2016
Session Poster lunch
Topics Thoracic Malignancies
Pathology/Molecular Biology
Translational Research
Basic Scientific Principles
Basic Principles in the Management and Treatment (of cancer)
Presenter Chiara Lazzari
Citation Journal of Thoracic Oncology (2016) 11 (supplement 4): S57-S166. S1556-0864(16)X0004-4
Authors C. Lazzari1, N. Karachaliou2, A. Verlicchi3, I. Chaib4, S. Marin4, A. Gkountakos5, S. Pilotto6, J.L. Ramírez Serrano4, F. de Marinis1, R. Rosell7
  • 1Divisione Di Oncologica Toracica, Istituto Europeo di Oncologia - IEO, 20141 - Milano/IT
  • 2Oncology, IOR, Quirón-Dexeus University Institute, 08028 - Barcelona/ES
  • 3Oncology, Ospedale Sta Maria delle Croci, 48121 - Ravenna/IT
  • 4Laboratory Of Cellular And Molecular Biology, Catalan Institute of Oncology (ICO Badalona), Hospital Germans Trias i Pujol, 08916 - Badalona/ES
  • 5Laboratory Of Cellular And Molecular Biology, University of Crete, School of Medicine, 71003 - Heraklion/GR
  • 6Department Of Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, 37122 - Verona/IT
  • 7Medical Oncology Service, Catalan Institute of Oncology (ICO Badalona), Hospital Germans Trias i Pujol, 08916 - Badalona/ES



KRAS mutations – present in 20–30% of patients with LAC – represent an unmet medical need in lung cancer therapy. MEK inhibition has shown to be interesting but still has modest efficacy when combined with docetaxel in KRASm LAC patients. STAT3 activation and AXL-mediated epithelial-to-mesenchymal transition has been associated with resistance to MEK inhibition. p21-activated kinase 1 (PAK1) regulates ERK activation through phosphorylation of MEK and its role in KRASm LAC warrants further investigation. The objective of our study is to define the role of STAT3, AXL and PAK1 in KRASm LAC cell lines and develop a rationale for combinatorial strategies in KRASm tumors.


The mRNA expression of STAT3, AXL and PAK1 were examined by quantitative real-time PCR in 4 KRASm LAC cell lines: H23, A549, H460 and Calu-6. The MEK inhibitor selumetinib was combined with 3 classes of drugs: STAT3 (TPCA-1, evodiamine), AXL (R428) and PAK1 (R-ketorolac) inhibitors. Cell viability was assessed by the thiazolyl blue assay and the combination index (CI) was calculated for the analysis of drug interactions.


Among the cell lines examined, the H23 had high and the A549 moderate STAT3 mRNA expression. The combination of selumetinib with a STAT3 inhibitor was synergistic in the H23 but antagonistic in the A549, as shown by CIs significantly 1, respectively. However, the combination of selumetinib with an AXL inhibitor was antagonistic in the A549 and synergistic in the H23, which have high and moderate AXL mRNA expression, respectively. The A549 cell line was found to additionally overexpress PAK1 and the combination of selumetinib with a PAK1 inhibitor is ongoing. The H460 and Calu-6 cell lines have moderate or low expression of STAT3, AXL and PAK1. Further cell viability experiments as well as immunoblotting and biomarkers analysis in clinical tumor samples are ongoing.


Based on previously published knowledge, we have tried to identify molecules that have synthetic lethal inhibition when combined with MEK inhibition for KRASm LAC. Our data, until now, identify STAT3 and AXL as potential biomarkers and the targeting of STAT3 and AXL as a potential synergistic strategy to combine with MEK inhibition.

Clinical trial identification

Legal entity responsible for the study

Catalan Institute of Oncology Germans Trias i Pujol Health Sciences Institute and Hospital Campus Can Ruti 08916 Badalona, Barcelona Spain


Funding from Obra Social La Caixa Foundation and also supported by a grant from the Red Temática de Investigación Cooperativa en Cáncer (RTICC; grant RD12/0036/ 0072)


All authors have declared no conflicts of interest.