Targeting of neuroblastoma cells through Kynurenine-AHR pathway inhibition

• Published in: The FEBS journal 2024-05, Vol.291 (10), p.2172-2190
• Main Authors: Dos Santos, Igor Lopes, Mitchell, Michael, Nogueira, Pedro A S, Lafita-Navarro, M Carmen, Perez-Castro, Lizbeth, Eriom, Joyane, Kilgore, Jessica A, Williams, Noelle S, Guo, Lei, Xu, Lin, Conacci-Sorrell, Maralice
• Format: Article
• Language: English
• Subjects: Antineoplastic drugs; Basic Helix-Loop-Helix Transcription Factors - antagonists & inhibitors; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; Chemotherapy; Children; Correlation analysis; Dioxygenase; Gene Expression Regulation, Neoplastic - drug effects; Humans; Immunomodulation; Indoleamine-Pyrrole 2,3,-Dioxygenase - antagonists & inhibitors; Indoleamine-Pyrrole 2,3,-Dioxygenase - genetics; Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism; Irinotecan; Kynurenine - metabolism; Malignancy; Neuroblastoma; Neuroblastoma - drug therapy; Neuroblastoma - genetics; Neuroblastoma - metabolism; Neuroblastoma - pathology; Neuroblasts; Physiological effects; Receptors, Aryl Hydrocarbon - antagonists & inhibitors; Receptors, Aryl Hydrocarbon - genetics; Receptors, Aryl Hydrocarbon - metabolism; Retinoic acid; Signal Transduction - drug effects; Synergistic effect; Therapeutic targets; Tretinoin - pharmacology; Tryptophan; Tryptophan Oxygenase - antagonists & inhibitors; Tryptophan Oxygenase - genetics; Tryptophan Oxygenase - metabolism
• ISSN: 1742-464X; 1742-4658; 1742-4658
• DOI: 10.1111/febs.17109

Neuroblastoma poses significant challenges in clinical management. Despite its relatively low incidence, this malignancy contributes disproportionately to cancer-related childhood mortality. Tailoring treatments based on risk stratification, including MYCN oncogene amplification, remains crucial, yet high-risk cases often confront therapeutic resistance and relapse. Here, we explore the aryl hydrocarbon receptor (AHR), a versatile transcription factor implicated in diverse physiological functions such as xenobiotic response, immune modulation, and cell growth. Despite its varying roles in malignancies, AHR's involvement in neuroblastoma remains elusive. Our study investigates the interplay between AHR and its ligand kynurenine (Kyn) in neuroblastoma cells. Kyn is generated from tryptophan (Trp) by the activity of the enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2). We found that neuroblastoma cells displayed sensitivity to the TDO2 inhibitor 680C91, exposing potential vulnerabilities. Furthermore, combining TDO2 inhibition with retinoic acid or irinotecan (two chemotherapeutic agents used to treat neuroblastoma patients) revealed synergistic effects in select cell lines. Importantly, clinical correlation analysis using patient data established a link between elevated expression of Kyn-AHR pathway genes and adverse prognosis, particularly in older children. These findings underscore the significance of the Kyn-AHR pathway in neuroblastoma progression, emphasizing its potential role as a therapeutic target.