Etienne Giroux Leprieur1, Thibault Vieira2, Martine Antoine3, Nathalie Rozensztajn4, Nathalie Rabbe2, Anne-Marie Ruppert2, Armelle Lavole4, Jacques Cadranel2, Marie Wislez5. 1. 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. 2. Theranoscan, UPMC University of Paris VI, Sorbonne Universités, Paris, France; Service de Pneumologie, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Paris, France. 3. Theranoscan, UPMC University of Paris VI, Sorbonne Universités, Paris, France; Service d'Anatomie Pathologique, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Paris, France. 4. Service de Pneumologie, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Paris, France. 5. 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.
Abstract
INTRODUCTION: 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. PATIENTS AND METHODS: 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). RESULTS: 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. CONCLUSION: The Shh pathway is associated with resistance to platinum-based chemotherapy in NSCLC.
INTRODUCTION: 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. PATIENTS AND METHODS: 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). RESULTS: 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. CONCLUSION: The Shh pathway is associated with resistance to platinum-based chemotherapy in NSCLC.
Authors: B Mohelnikova-Duchonova; M Kocik; B Duchonova; V Brynychova; M Oliverius; J Hlavsa; E Honsova; J Mazanec; Z Kala; I Ojima; D J Hughes; J E Doherty; H A Murray; M A Crockard; R Lemstrova; P Soucek Journal: Pharmacogenomics J Date: 2016-08-30 Impact factor: 3.550
Authors: Norashikin Zakaria; Nazilah Abdul Satar; Noor Hanis Abu Halim; Siti Hawa Ngalim; Narazah Mohd Yusoff; Juntang Lin; Badrul Hisham Yahaya Journal: Front Oncol Date: 2017-05-05 Impact factor: 6.244