Sonic Hedgehog Pathway Activation Is Associated With Resistance to Platinum-Based Chemotherapy in Advanced Non-Small-Cell Lung Carcinoma

Autor: T. Vieira, N. Rozensztajn, Etienne Giroux Leprieur, Anne-Marie Ruppert, Nathalie Rabbe, Martine Antoine, Jacques Cadranel, Armelle Lavolé, Marie Wislez
Přispěvatelé: Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Theranoscan, Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Pneumologie - Oncologie Thoracique - Maladies Pulmonaires Rares [CHU Tenon], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'anatomie pathologique [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Rok vydání: 2015
Předmět:
0301 basic medicine
Oncology
Male
Cancer Research
Pyridines
medicine.medical_treatment
sarcomatoid carcinoma
Platinum Compounds
Cohort Studies
0302 clinical medicine
Carcinoma
Non-Small-Cell Lung
Antineoplastic Combined Chemotherapy Protocols
Medicine
Anilides
biology
chemoresistance
Nuclear Proteins
Middle Aged
Hedgehog signaling pathway
3. Good health
non-small cell carcinoma
Sonic Hedgehog
030220 oncology & carcinogenesis
Female
medicine.drug
Signal Transduction
Pulmonary and Respiratory Medicine
Adult
Transcriptional Activation
medicine.medical_specialty
animal structures
Kruppel-Like Transcription Factors
Vismodegib
[SDV.CAN]Life Sciences [q-bio]/Cancer
Zinc Finger Protein Gli2
Zinc Finger Protein GLI1
03 medical and health sciences
GLI1
Internal medicine
Cell Line
Tumor
Carcinoma
Humans
Hedgehog Proteins
Lung cancer
Sarcomatoid carcinoma
Neoplasm Staging
Cisplatin
Chemotherapy
business.industry
medicine.disease
Survival Analysis
030104 developmental biology
Drug Resistance
Neoplasm
biology.protein
business
Gli
Zdroj: Clinical Lung Cancer
Clinical Lung Cancer, 2015, 17 (4), pp.301-308. ⟨10.1016/j.cllc.2015.12.007⟩
Clinical Lung Cancer, Elsevier, 2015, 17 (4), pp.301-308. ⟨10.1016/j.cllc.2015.12.007⟩
ISSN: 1938-0690
1525-7304
DOI: 10.1016/j.cllc.2015.12.007⟩
Popis: International audience; Introduction : Chemoresistance is a major challenge in the treatment of advanced non-small cell lung cancer (NSCLC). As the Sonic Hedgehog (Shh) pathway is reactivated in NSCLC, we investigated an association between chemoresistance and Shh activation.Materials 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 by immunohistochemistry (IHC) (quantitative score). In vitro treatment studies with cisplatin, vismodegib (Shh-pathway inhibitor) or both were performed on NSCLC cell lines (H322 and A549) and on primary cultures from patients with sarcomatoid carcinoma (n=4).Results : Twelve patients were 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=0.35). Gli2 expression was more often positive in the r-patients (41.7% versus 8.3%, p=0.02). Progression-free survival (PFS) and overall survival (OS) in patients with Gli2-positive score were 2.1 and 8.0 months, respectively, versus 6.7 and 18.0 months in patients with Gli2-negative score (p=0.03; p=0.002). In multivariate analysis, Gli2 score was independently correlated with PFS (hazard ratio [HR]=2.64; 95% confidence interval [CI]: 1.05-6.63; p=0.04) and OS (HR=4.36; 95% CI: 1.67-11.36; p=0.003). The sarcomatoid carcinoma cell lines were more resistant to cisplatin than 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.
Databáze: OpenAIRE
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