title: Sonic Hedgehog Pathway Activation Is Associated With Resistance to Platinum-Based Chemotherapy in Advanced Non-Small-Cell Lung Carcinoma.
abstract: Chemoresistance is a major challenge in the treatment of advanced non-small-cell lung cancer (NSCLC). Because the Sonic hedgehog (Shh) pathway is reactivated in NSCLC, we investigated an association between chemoresistance and Shh activation.
  
  
  
  From a cohort of 178 patients with advanced NSCLC treated with platinum-based chemotherapy as first-line treatment, we selected all surgical tumor samples at diagnosis (n = 36). Shh activation was evaluated through Gli1 and Gli2 expression using immunohistochemistry (quantitative score). In vitro treatment studies with cisplatin or vismodegib (Shh pathway inhibitor), or both, were performed on NSCLC cell lines (H322 and A549) and primary cultures from patients with sarcomatoid carcinoma (n = 4).
  
  
  
  Of the 36 patients, 12 had NSCLC refractory to chemotherapy (R-patients, 33.3%) and 24 had controlled disease (C-patients). Gli1 expression did not differ between the R- and C-patients (P = .35). Gli2 expression was more often positive in the R-patients (41.7% vs. 8.3%; P = .02). Progression-free survival (PFS) and overall survival (OS) in patients with a Gli2-positive score was 2.1 and 8.0 months, respectively, compared with 6.7 and 18.0 months for patients with a Gli2-negative score (P = .03 and P = .002, respectively). On multivariate analysis, the Gli2 score correlated independently with PFS (hazard ratio [HR], 2.64; 95% confidence interval [CI], 1.05-6.63; P = .04) and OS (HR, 4.36; 95% CI, 1.67-11.36; P = .003). The sarcomatoid carcinoma cell lines were more resistant to cisplatin than were the H838 and A549 cell lines. The cisplatin-vismodegib combination displayed a synergistic cytotoxic effect in the most chemoresistant cells in vitro.
  
  
  
  The Shh pathway is associated with resistance to platinum-based chemotherapy in NSCLC.
authors.affiliation: Theranoscan, UPMC University of Paris VI, Sorbonne Universités, Paris, France; Service de Pneumologie et Oncologie Thoracique, Assistance Publique-Hôpitaux de Paris, Hôpital Ambroise Paré, EA 4340 Biomarqueurs en Cancérologie et Onco-Hématologie, Université Versailles Saint Quentin en Yvelines, Boulogne-Billancourt, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Giroux Leprieur
authors.affiliation: Theranoscan, UPMC University of Paris VI, Sorbonne Universités, Paris, France; Service de Pneumologie, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Thibault
authors.initials: T
authors.lastname: Vieira
authors.affiliation: Theranoscan, UPMC University of Paris VI, Sorbonne Universités, Paris, France; Service d'Anatomie Pathologique, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Antoine
authors.affiliation: Service de Pneumologie, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rozensztajn
authors.affiliation: Theranoscan, UPMC University of Paris VI, Sorbonne Universités, Paris, France; Service de Pneumologie, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rabbe
authors.affiliation: Theranoscan, UPMC University of Paris VI, Sorbonne Universités, Paris, France; Service de Pneumologie, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Ruppert
authors.affiliation: Service de Pneumologie, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Armelle
authors.initials: A
authors.lastname: Lavole
authors.affiliation: Theranoscan, UPMC University of Paris VI, Sorbonne Universités, Paris, France; Service de Pneumologie, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Cadranel
authors.affiliation: Theranoscan, UPMC University of Paris VI, Sorbonne Universités, Paris, France; Service de Pneumologie, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Paris, France. Electronic address: marie.wislez@tnn.aphp.fr.
authors.forename: Marie
authors.initials: M
authors.lastname: Wislez
mesh_terms: D000328:Adult; D000813:Anilides / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D045744:Cell Line, Tumor; D015331:Cohort Studies; D019008:Drug Resistance, Neoplasm; D005260:Female; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000378:metabolism*; D017671:Platinum Compounds / Q000627:therapeutic use*; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D015533:Transcriptional Activation / Q000187:drug effects; D000071676:Zinc Finger Protein GLI1 / Q000378:metabolism; D000075746:Zinc Finger Protein Gli2
chemical_list: D000813:Anilides; C400551:GLI1 protein, human; C082593:GLI2 protein, human; D053823:Hedgehog Proteins; C538724:HhAntag691; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D017671:Platinum Compounds; D011725:Pyridines; C509239:SHH protein, human; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2
keywords: Chemoresistance; Gli; NSCLC; Sarcomatoid carcinoma; Shh