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

Clin Lung Cancer. 2016 Jul;17(4):301-8. doi: 10.1016/j.cllc.2015.12.007. Epub 2015 Dec 17.

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.

Keywords: Chemoresistance; Gli; NSCLC; Sarcomatoid carcinoma; Shh.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anilides / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Carcinoma, Non-Small-Cell Lung / diagnosis
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / mortality
  • Cell Line, Tumor
  • Cohort Studies
  • Drug Resistance, Neoplasm
  • Female
  • Hedgehog Proteins / metabolism*
  • Humans
  • Kruppel-Like Transcription Factors / metabolism*
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Nuclear Proteins / metabolism*
  • Platinum Compounds / therapeutic use*
  • Pyridines / pharmacology
  • Signal Transduction / drug effects
  • Survival Analysis
  • Transcriptional Activation / drug effects
  • Zinc Finger Protein GLI1 / metabolism
  • Zinc Finger Protein Gli2

Substances

  • Anilides
  • GLI1 protein, human
  • GLI2 protein, human
  • Hedgehog Proteins
  • HhAntag691
  • Kruppel-Like Transcription Factors
  • Nuclear Proteins
  • Platinum Compounds
  • Pyridines
  • SHH protein, human
  • Zinc Finger Protein GLI1
  • Zinc Finger Protein Gli2