76P - An innovative co-targeting of signal transducer and activator of transcription 3 (STAT3) and Src-YAP pathways in EGFR mutant non-small cell lung ca...

Date 15 April 2016
Event European Lung Cancer Conference 2016 (ELCC) 2016
Session Poster lunch
Topics Thoracic malignancies
Translational Research
Basic Principles in the Management and Treatment (of cancer)
Presenter Niki Karachaliou
Citation Journal of Thoracic Oncology (2016) 11 (supplement 4): S57-S166. S1556-0864(16)X0004-4
Authors N. Karachaliou1, I. Chaib2, S. Pilotto3, J. Codony4, X. Cai5, X. Li6, S. Marin2, C. Zhou6, P. Cao5, R. Rosell2
  • 1Oncology, IOR, Quirón-Dexeus University Institute, 08028 - Barcelona/ES
  • 2Laboratory Of Celluar And Molecular Biology, Catalan Institute of Oncology (ICO Badalona), Hospital Germans Trias i Pujol, 08916 - Badalona/ES
  • 3Oncology, AOU Integrata Verona "Borgo Roma", 37134 - Verona/IT
  • 4Quiron-dexeus, University Institute, Laboratory, Pangaea Biotech SL, 08028 - Barcelona/ES
  • 5Laboratory Of Celluar And Molecular Biology, Hospital of Integrated Traditional Chinese and Western Medicine, 210028 - Nanjing/CN
  • 6Dept. Of Lung Cancer Immunology, Shangai Pulmonary Hospital, Tongji University School of Medicine, 200082 - Shanghai/CN

Abstract

Background

Although EGFR tyrosine kinase inhibitors (TKIs) collapse a network of downstream signaling in EGFR mutant NSCLC, they simultaneously promote lateral rescue pathways, like STAT3 and Src-YAP, that render targeting ineffective. Herein we demonstrate that EGFR TKIs cannot abrogate STAT3 and Src in EGFR mutant NSCLC, providing a rationale for combining EGFR TKIs with STAT3 (e.g. TPCA-1) and Src (e.g. saracatinib) inhibitors. The prognostic and predictive impact of STAT3 and YAP was investigated in clinical tumor samples.

Methods

Cell viability and colony formation assays, western blotting and quantitative-real time PCR were performed in cell lines and clinical tumor samples. A PC-9 xenograft model was constructed for in vivo experiments.

Results

STAT3 phosphorylation on the tyrosine residue 705 (pSTAT3 Y705) was increased in a time- and dose-dependent manner with gefitinib alone in PC-9 cells (EGFR exon 19 deletion). pSTAT3 Y705 was diminished with the combination of gefitinib+TPCA-1. Gefitinib+TPCA-1 did not inhibit YAP activation through Src family kinase phosphorylation on Y357. Gefitinib+saracatinib inhibited pYAP Y357 but not pSTAT3 Y705. The triple combination of gefitinib+TPCA-1+saracatinib abrogated both pSTAT3 Y705 and pYAP Y357. Fewer colonies were formed with the triple combination compared to gefitinib alone or double combinations in PC-9 cells. The triple combination was highly synergistic in PC-9 and H1975 (L858R+ T790M EGFR mutation) cells. In a PC-9 xenograft model, the triple combination led to a greater effect than gefitinib alone or the double combinations. In 64 EGFR mutant NSCLC patients (p) treated with first line EGFR TKIs, high STAT3 or YAP mRNA expression was significantly correlated with shorter median progression-free survival (mPFS) [9.6 months (m) vs 18.4m (P 

Conclusions

Single EGFR TKI treatment can no longer be considered adequate for p with EGFR mutant NSCLC and a clinical trial co-targeting EGFR, STAT3 and Src is warranted

Clinical trial identification

Legal entity responsible for the study

Catalan Institute of Oncology Germans Trias i Pujol Health Sciences Institute and Hospital Badalona, Barcelona, Spain IOR, Quirón-Dexeus University Institute, Barcelona, Spain

Funding

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

Disclosure

All authors have declared no conflicts of interest.