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Sonic Hedgehog Pathway Activation Is Associated With Resistance to Platinum-Based Chemotherapy in Advanced
Etienne Giroux Leprieur1, Thibault Vieira2, Martine Antoine3
1Theranoscan, 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.
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.
Insights
Chemoresistance in non-small-cell lung cancer (NSCLC) is linked to the Sonic hedgehog (Shh) pathway. Gli2 activation in NSCLC patients correlates with poorer survival, suggesting Shh as a therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Chemoresistance presents a significant obstacle in treating advanced non-small-cell lung cancer (NSCLC).
- The Sonic hedgehog (Shh) signaling pathway is known to be reactivated in NSCLC.
- Investigating the link between Shh pathway activation and chemoresistance is crucial for developing effective treatments.
Purpose of the Study:
- To explore the association between chemoresistance and Shh pathway activation in advanced NSCLC.
- To evaluate Gli1 and Gli2 expression as potential biomarkers for chemoresistance.
- To assess the efficacy of Shh pathway inhibition in combination with chemotherapy.
Main Methods:
- Analysis of tumor samples from 36 advanced NSCLC patients treated with platinum-based chemotherapy.
- Immunohistochemical evaluation of Gli1 and Gli2 expression.
- In vitro studies using NSCLC cell lines and primary cultures treated with cisplatin and/or vismodegib (Shh inhibitor).
Main Results:
- Gli2 expression was significantly more frequent in chemotherapy-refractory patients (41.7%) compared to controlled patients (8.3%).
- Patients with positive Gli2 scores exhibited shorter progression-free survival (2.1 months) and overall survival (8.0 months) than those with negative Gli2 scores.
- Multivariate analysis confirmed Gli2 positivity as an independent predictor of worse PFS and OS.
- In vitro, a combination of cisplatin and vismodegib showed synergistic cytotoxicity in chemoresistant NSCLC cells.
Conclusions:
- The Shh pathway, particularly Gli2 activation, is associated with resistance to platinum-based chemotherapy in NSCLC.
- Gli2 expression may serve as a predictive biomarker for chemoresistance in NSCLC patients.
- Targeting the Shh pathway in combination with chemotherapy could be a promising strategy to overcome chemoresistance in NSCLC.
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