1527P - Differential expression profile of lung squamous cell carcinoma (LSCC) and druggable targets to be combined with necitumumab (N)

Date 10 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Translational Research
Basic Principles in the Management and Treatment (of cancer)
Presenter Alberto Verlicchi
Citation Annals of Oncology (2016) 27 (6): 526-544. 10.1093/annonc/mdw392
Authors A. Verlicchi1, C. Lazzari2, C. Codony Servat3, M.A. Molina Vila3, J. Codony Servat3, I. Chaib4, J.L. Ramírez Serrano5, N. Karachaliou6, C. Dazzi1, R. Rosell5
  • 1Dipartimento Di Oncologia/ematologia, Ospedale Civile di Ravenna - S.ta Maria delle Croci, 48121 - Ravenna/IT
  • 2Divisione Di Oncologica Toracica, Istituto Europeo di Oncologia, 20141 - Milano/IT
  • 3Laboratory Of Cellular And Molecular Biology, Pangaea Biotech SL, IOR Quirón-Dexeus University Institute, 08028 - Barcelona/ES
  • 4Laboratory Of Cellular And Molecular Biology, Institut d'Investigació en Ciències Germans Trias i Pujol, 08916 - Badalona/ES
  • 5Translational Research Unit, Laboratory Of Molecular Biology, Catalan Institute of Oncology (ICO Badalona), Hospital Germans Trias i Pujol, 08916 - Badalona/ES
  • 6Medical Oncology Service, Instituto Oncológico Dr Rosell (IOR), Hospital Universitario Quirón-Dexeus, 08028 - Barcelona/ES

Abstract

Background

LSCC lacks effective targeted therapies. EGFR is commonly expressed in LSCC and N, an anti-EGFR monoclonal antibody (mAb), is the only approved targeted therapy that with chemotherapy provides a small (clinically irrelevant) survival benefit as 1st-line treatment in metastatic LSCC. AXL, STAT3 or YAP1 pathway activation, and hedgehog-GLI signaling have been described as mechanisms of resistance to anti-EGFR therapy. p21-activated kinase 1 (PAK1) is overexpressed in LSCC, diminishing the efficacy of anti-EGFR mAbs. Herein, we evaluate the relevance of these pathways in LSCC cell lines, illustrating the potential for synthetic lethal approaches.

Methods

AXL (and its ligand GAS6), STAT3, YAP1, GLI1/2 and PAK1 mRNA expression were examined by quantitative real-time PCR in 6 LSCC cell lines: H2286, HCC366, H520, H1703, SK-MES1, and EBC1. Cell viability was assessed by the thiazolyl blue assay after treatment with evodiamine (STAT3i), R428 (AXLi), ivermectin (dual YAP1-PAK1i) or GANT61 and mebendazole (GLIi) alone or in combination with 25ug/ml of N.

Results

EGFR was homogeneously overexpressed in all tested cell lines except H520 that lacks EGFR expression. Moderate STAT3 mRNA expression was detected in SK-MES1 cells in which treatment with evodiamine synergistically increased the effect of N alone. The dual YAP1-PAK1i, ivermectin was more active (IC50 3-7uM) in the H1703 and H2286 YAP1 overexpressing cells in comparison with the rest of YAP1 low expressing cells. No correlation was found between PAK1 expression and sensitivity to ivermectin in the tested LSCC cell lines. High GLI1/2 expression and relative sensitivity to the GLI1/2i, GANT61 or mebendazole (IC50 2-3uM) were detected in the H2286 cells. Among our LSCC cell lines, H2286 also had the highest AXL and GAS6 mRNA expression. Western blotting analysis, as well as further cell viability experiments with drugs alone and in combination with N, are ongoing.

Conclusions

LSCC is a heterogeneous disease, in which common signaling pathways dictate distinct pathologic outputs. The awareness of these differences is necessary while planning efficient strategies to improve the scant clinical benefit with EGFR mAbs.

Clinical trial identification

Legal entity responsible for the study

N/A

Funding

This work was supported by grants from the La Caixa Foundation and Red Tematica de Investigacion Cooperativa en Cancer (RTICC; grant RD12/0036/ 0072).

Disclosure

All authors have declared no conflicts of interest.