1604P - Role of Hedgehog pathway in mediating resistance to EGFR-inhibitors in non-small cell lung cancer

Date 28 September 2014
Event ESMO 2014
Session Poster Display session
Topics Thoracic Malignancies
Translational Research
Basic Principles in the Management and Treatment (of cancer)
Presenter Carminia Maria Della Corte
Citation Annals of Oncology (2014) 25 (suppl_4): iv546-iv563. 10.1093/annonc/mdu358
Authors C.M. Della Corte, M. Fasano, D. Vitagliano, T. Troiani, E. Martinelli, F. Ciardiello, F. Morgillo
  • Medical Oncology, Second University of Naples, 80131 - Napoli/IT



Tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) are treatment choices in the management of EGFR wild-type (WT) non-small cell lung cancer (NSCLC) patients who progressed on previous chemotherapy. However, development of resistance, even in responders, is sooner or later observed. Recently our group demonstrated the acquisition of a mesenchymal phenotype in an in vitro model of NSCLC cell lines with acquired resistance to anti-EGFR TKIs. The Hedgehog (Hh) signaling pathway has emerged as an important mediator of carcinogenesis and cancer metastases. The aim of this work is to explore the Hh role in EGFR TKIs resistence.


We studied the activation of Hh signaling (Shh, Gli1, PTCH, Smo) in a panel of NSCLC cell lines (H460, H1299, A549, GLC82, CALU-3, H322, H358), harbouring WT EGFR, and with different sensitivity to two EGFR TKIs, gefitinib and erlotinib. Immunohistochemistry of PTCH and Shh was performed on 33 histological samples of NSCLC patients treated with erlotinib in second/third line of therapy.


Experiments showed a strong expression of Shh, Smo, PTCH and Gli1 in NSCLC cell lines resistant to EGFR TKIs, indicating activation of Hh signalling in such cells. Treatment with different Smo inhibitors, cyclopamine, LDE225 or vismodegib, in combination with EGFR inhibitors, strongly inhibited the proliferation of resistant NSCLC cell lines and induced apoptosis. Furthermore, combined treatment blocked the invasive and migratory behavior of resistant cells along with a complete inhibition of PI3K/Akt and MAPK phosphorylation. Preliminary data, obtained from the immunohistochemical analysis of Hh related molecules, showed higher expression of Shh and PTCH in cancer cells as compared to surrounding normal tissue. Among 20 patients, which received EGFR TKI in second/third line of therapy, those presenting a lower Shh and PTCH expression experienced a trend toward a better progression free survival.


Our study should provide the opportunity to better understand the role of HH pathway in mediating resistance to anti-EGFR TKIs and to design new strategies to be easily transferred into clinical practice.


All authors have declared no conflicts of interest.