Baseline hedgehog pathway activation and increase of plasma wnt1 protein are associated with resistance to immune checkpoint inhibitors in advanced non-small-cell lung cancer
| Autor: | Thierry Chinet, Camille Mehlman, Violaine Giraud, Adrien Costantini, Coraline Dumenil, Jean-François Emile, J. Ouaknine, Jennifer Dumoulin, Etienne Giroux Leprieur, Paul Takam Kamga, Catherine Julie |
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| Přispěvatelé: | Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Hôpital Ambroise Paré [AP-HP] |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Oncology
Cancer Research medicine.medical_specialty Gli1 Resistance [SDV.CAN]Life Sciences [q-bio]/Cancer Immune checkpoint inhibitor lcsh:RC254-282 [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract Article 03 medical and health sciences Wnt Plasma 0302 clinical medicine Non-small cell lung cancer GLI1 WNT2 Interquartile range Internal medicine medicine Sonic hedgehog Lung cancer Hedgehog 030304 developmental biology 0303 health sciences biology business.industry Wnt signaling pathway [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Hedgehog signaling pathway 3. Good health Sonic Hedgehog 030220 oncology & carcinogenesis Beta-catenin biology.protein business |
| Zdroj: | Cancers Cancers, MDPI, 2021, 13 (5), pp.1107. ⟨10.3390/cancers13051107⟩ Volume 13 Issue 5 Cancers, Vol 13, Iss 1107, p 1107 (2021) |
| ISSN: | 2072-6694 |
| Popis: | Simple Summary Wnt and Hedgehog (Hh) pathways are associated with stemness profile and with resistance to anti-tumor therapies. Pre-clinical data have suggested a role of these pathways in resistance to immune checkpoint inhibitors (ICIs). Here we evaluated the expression and levels of Shh and Wnt molecules both in plasma and tumor samples in a prospective cohort of 63 consecutive NSCLC patients treated with ICIs. We found that baseline Hh activation as assessed by nuclear staining of Gli1 was associated with poor outcome and high primary resistance rate. Increase of plasma Wnt1 during treatment was associated with resistance to ICIs. This is the first study to our knowledge to find an association between the Hh and Wnt pathways and resistance to ICIs in advanced NSCLC patients. We believe that these results are important to understand the molecular mechanisms associated with resistance to ICIs, and ultimately to improve future treatment strategies. Abstract Hedgehog (Hh) and Wingless-type (Wnt) pathways are associated with resistance to immune checkpoint inhibitors (ICIs) in preclinical studies. This study aimed to assess the association between expression and activation levels of Wnt and Sonic Hedgehog (Shh) pathways and resistance to ICIs in advanced NSCLC patients treated with ICI. Hh and Wnt pathways activation was assessed by immunohistochemistry (Gli1 and beta-catenin) on corresponding tumor tissues, and by plasma concentrations of Shh and Wnt (Wnt1, Wnt2 and Wnt3) at ICI introduction and at the first clinical evaluation. Sixty-three patients were included, with 36 patients (57.1%) with available tissue. Response rate was lower in Gli1+ NSCLC (20.0%) compared to Gli1 negative (Gli-) NSCLC (55.6%) (p = 0.015). Rate of primary resistance was 69.8%, vs. 31.2%, respectively (p = 0.04), and median progression-free survival (PFS) was 1.9 months (interquartile range (IQR) 1.2–5.7) vs. 6.1 months (1.6–26.0), respectively (p = 0.08). Median PFS and overall survival were shorter in case of increase of Wnt1 concentration during ICI treatment compared to other patients: 3.9 months vs. 11.2 months (p = 0.008), and 15.3 months vs. not reached (p = 0.003). In conclusion, baseline activation of Hh pathway and increase of Wnt1 concentrations during ICI treatment were associated with poor outcome in NSCLC patients treated with ICIs. |
| Databáze: | OpenAIRE |
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