Inclusion of JNK-independent drugs within multiagent chemotherapy improves response in relapsed high-risk
Jeremy Z R Han1, Monica Phimmachanh1, Jordan F Hastings1
1Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
Abstract:
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.
Insights
Chemoresistant neuroblastoma can be overcome by targeting c-Jun amino-terminal kinase (JNK)-independent apoptosis pathways. New drug combinations improve treatment efficacy in relapsed cancers.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Chemoresistance significantly worsens prognosis in neuroblastoma.
- Heterogeneity in c-Jun amino-terminal kinase (JNK) signaling drives non-genetic chemoresistance in neuroblastoma.
- JNK pathway impairment presents a major obstacle for effective chemotherapy in relapsed neuroblastoma.
Purpose of the Study:
- To identify JNK-independent drugs that induce apoptosis in chemoresistant neuroblastoma.
- To investigate synergistic mechanisms between novel JNK-independent agents and standard chemotherapies.
- To evaluate the efficacy of combined therapies in preclinical models of relapsed neuroblastoma.
Main Methods:
- Developed a mathematical model of JNK activation.
- Conducted a pediatric-focused drug screen to identify JNK-independent apoptosis inducers.
- Utilized functional genomics to elucidate synergistic mechanisms.
- Tested drug efficacy in patient-derived xenograft models.
Main Results:
- Identified approved oncology drugs inducing apoptosis independently of JNK.
- Discovered that synergy arises from differential apoptotic network component utilization, not direct target engagement.
- Demonstrated significant improvement in treatment response in relapsed neuroblastoma models using combined JNK-independent and standard chemotherapy.
Conclusions:
- JNK-independent drugs offer a promising strategy to overcome chemoresistance in neuroblastoma.
- Combination therapy targeting JNK-independent pathways enhances efficacy in relapsed settings.
- Novel therapeutic approaches are crucial for improving outcomes in relapsed neuroblastoma.
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