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Poly-therapy with EGFR, STAT3 and Src-YAP1 signaling pathway inhibition; A breakthrough for EGFR mutant NSCLC

Date

08 Oct 2016

Session

Poster Display

Presenters

Niki Karachaliou

Citation

Annals of Oncology (2016) 27 (6): 411-415. 10.1093/annonc/mdw382

Authors

N. Karachaliou1, I. Chaib2, X. Cai3, X. Li4, A.F. Cardona5, G. López-Vivanco6, A. Vergnenegre7, J.M. Sanchez Torres8, M. Provencio9, F. de Marinis10, E. Carecereny11, N. Reguart12, R. García Campelo13, S. Viteri1, M.A. Molina Vila14, C. Zhou4, P. Cao3, P. Ma15, T. Bivona16, R. Rosell17

Author affiliations

  • 1 Medical Oncology Service, Instituto Oncológico Dr Rosell (IOR), Hospital Universitario Quirón-Dexeus, 08028 - Barcelona/ES
  • 2 Laboratory Of Cellular And Molecular Biology, Institut d'Investigació en Ciències Germans Trias i Pujol, 08916 - Badalona/ES
  • 3 Laboratory Of Cellular And Molecular Biology, Academy of Traditional Chinese Medicine, 210028 - Nanjing/CN
  • 4 Lung Cancer Oncology & Immunology, Tongji Hospital of Tongji University, 200433 - Shanghai/CN
  • 5 Medical Oncology, Clinica del Country, 318 - Bogota/CO
  • 6 Medical Oncology, Hospital de Cruces, 48903 - Barakaldo/ES
  • 7 Service De L'uotc, CHU Limoges - Hopital Dupuytren, 87042 - Limoges/FR
  • 8 Medical Oncology Service, Hospital Universitario de La Princesa, 28006 - Madrid/ES
  • 9 Medical Oncology, Hospital Universitario Puerta de Hierro Majadahond, 28222 - Majadahonda/ES
  • 10 1 Unità Operativa Di Pneumologia Oncologica, Istituto Europeo di Oncologia, 20141 - Milano/IT
  • 11 Medical Oncology, Catalan Institute of Oncology (ICO Badalona), Hospital Germans Trias i Pujol, 08916 - Badalona/ES
  • 12 Medical Oncology, Hospital Clinic y Provincial de Barcelona, 08036 - Barcelona/ES
  • 13 Medical Oncology, Hospital Universitario a Coruna - a Corunac, 15006 - A Coruna/ES
  • 14 Laboratory Of Cellular And Molecular Biology, Pangaea Biotech SL, IOR Quirón-Dexeus University Institute, 08028 - Barcelona/ES
  • 15 Solid Tumor Oncology, West Virginia University Mary Babb Randolph Cancer Center, 26506 - Morgantown/US
  • 16 Hematology And Oncology, UCSF Helen Diller Family Comprehensive Cancer Center, 94115 - San Francisco/US
  • 17 Translational Research Unit, Laboratory Of Molecular Biology, Catalan Institute of Oncology (ICO Badalona), Hospital Germans Trias i Pujol, 08916 - Badalona/ES
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Resources

Background

Since the discovery of epidermal growth factor receptor (EGFR) mutations in 2004 as a driver alteration in non-small-cell lung cancer (NSCLC), mono-therapy with EGFR tyrosine kinase inhibitors (TKIs) is the conventional therapy. Growing evidence demonstrates that single EGFR TKI hyper-activates signal transducer and activator of transcription 3 (STAT3) almost immediately after starting treatment.

Methods

We conducted clinical and preclinical studies of key components of signaling pathways limiting EGFR TKI efficacy in EGFR mutant NSCLC.

Results

Gefitinib suppressed EGFR, ERK1/2 and AKT phosphorylation but increased STAT3 phosphorylation on the critical tyrosine residue 705 (pSTAT3-Tyr705) in a time and dose-dependent manner in PC9 cells. Gefitinib with TPCA-1 (STAT3 inhibitor) abolished pSTAT3-Tyr705. In addition to STAT3 activation, co-activation of Src-YES-associated protein 1 (YAP1) was also unexpectedly observed in our study. Gefitinib with TPCA-1 blocked STAT3, but not the YAP1 phosphorylation on tyrosine residue 357 by Src family kinases (SFKs). The triple combination of gefitinib, TPCA-1 and AZD0530 (SFK inhibitor) ablated both STAT3 and YAP1 phosphorylation and had greater effect than gefitinib alone or double combinations in vitro and in vivo.

High levels of STAT3 or YAP1 mRNA expression were associated with worse outcome to EGFR TKI in two independent cohorts of EGFR-mutant NSCLC patients. In the initial cohort of 64 patients, progression-free survival (PFS) was shorter among the patients with high STAT3 than among those with low STAT3 (hazard ratio [HR] for disease progression, 3.02; 95% confidence interval [CI], 1.54-5.93; P = 0.0013). PFS was shorter among the patients with high YAP1 than among those with low YAP1 (HR for disease progression, 2.57; 95%CI, 1.30-5.09; P = 0.0067). The results were similar in the validation cohort of 55 patients.

Conclusions

Co-targeting STAT3 and Src-YAP1-NOTCH signaling pathways could be a feasible solution that would have a major impact in prolonging cancer free survival in EGFR mutant NSCLC patients.

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), the National Natural Science Foundation of China (No. 81573680), and the Jiangsu Province Funds for Distinguished Young Scientists (No. BK20140049).

Disclosure

All authors have declared no conflicts of interest.

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