Inclusion of JNK-independent drugs within multiagent chemotherapy improves response in relapsed high-risk neuroblastoma
The acquisition of a chemoresistant state underlies poor prognosis in many cancers, including neuroblastoma. We previously demonstrated that heterogeneity in apoptosis induction through c-Jun amino-terminal kinase (JNK) promotes a form of nongenetic chemoresistance in neuroblastoma observable at both patient and single-cell levels. As the maintenance of this JNK-impaired state in the relapse setting is a substantial barrier to the efficacy of many standard-of-care chemotherapy drugs, we combined a mechanistic, mathematical model of JNK activation with a pediatric-focused drug screen and identified approved oncology drugs capable of inducing apoptosis in a JNK-independent manner. Functional genomics further revealed that synergy between these JNK-independent drugs and standard-of-care chemotherapies emerged from differential utilization of apoptotic network components, rather than from their direct mechanistic targets. Efficacy studies with patient-derived xenograft models also confirmed that including a JNK-independent drug within existing chemotherapy backbones significantly improved response in the relapse setting, where new approaches are urgently needed.
Authors
- Yolande E. I. O’Donnell (ORCID: https://orcid.org/0000-0003-1416-8886)
- Alvin Kamili (ORCID: https://orcid.org/0000-0002-4864-1195)
- Jordan F. Hastings (ORCID: https://orcid.org/0000-0003-2839-4358)
- Misaki S. Clearwater
- Murray D. Norris (ORCID: https://orcid.org/0000-0002-0632-4589)
- Toby N. Trahair (ORCID: https://orcid.org/0000-0002-3295-228X)
- Walter Kölch (ORCID: https://orcid.org/0000-0001-5777-5016)
- King Ho Leong (ORCID: https://orcid.org/0000-0001-7274-5560)
- Monica Phimmachanh (ORCID: https://orcid.org/0009-0001-2767-1168)
- Sharissa L. Latham (ORCID: https://orcid.org/0000-0003-1128-5315)
- David R. Croucher (ORCID: https://orcid.org/0000-0003-4965-8674)
- Angela R. M. Fontaine (ORCID: https://orcid.org/0000-0002-5032-8026)
- Jeremy Z. R. Han (ORCID: https://orcid.org/0000-0003-1310-6448)
- Boaz H. Ng (ORCID: https://orcid.org/0000-0002-2244-4636)
- Antonia L. Cadell (ORCID: https://orcid.org/0000-0002-3560-4125)
- Paul Timpson (ORCID: https://orcid.org/0000-0002-5514-7080)
- Michelle Haber (ORCID: https://orcid.org/0000-0003-2036-8817)
- Jamie I. Fletcher (ORCID: https://orcid.org/0000-0003-2949-9469)
- Jing Ni (ORCID: https://orcid.org/0000-0001-8254-683X)
- Dirk Fey (ORCID: https://orcid.org/0009-0005-7847-7479)
Institutions
- University College Dublin (IE)
- Garvan Institute of Medical Research (AU)
- Cancer Institute of New South Wales (AU)
- UNSW Sydney (AU)
- Children's Cancer Institute Australia (AU)
- Sydney Children's Hospital (AU)
Publication Details
- Journal
- Science Advances
- Published
- 2025-11-28
- DOI
- https://doi.org/10.1126/sciadv.ady5599
- Primary Topic
- Neuroblastoma Research and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00