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Published on: September 1, 2010
Mesenchymal-Type Neuroblastoma Cells Escape ALK Inhibitors
Ellen M Westerhout1, Mohamed Hamdi2, Peter Stroeken2
1Department of Oncogenomics, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands. e.m.westerhout@amsterdamumc.nl r.versteeg@amsterdamumc.nl.
Abstract:
Cancer therapy frequently fails due to the emergence of resistance. Many tumors include phenotypically immature tumor cells, which have been implicated in therapy resistance. Neuroblastoma cells can adopt a lineage-committed adrenergic (ADRN) or an immature mesenchymal (MES) state. They differ in epigenetic landscape and transcription factors, and MES cells are more resistant to chemotherapy. Here we analyzed the response of MES cells to targeted drugs. Activating anaplastic lymphoma kinase (ALK) mutations are frequently found in neuroblastoma and ALK inhibitors (ALKi) are in clinical trials. ALKi treatment of ADRN neuroblastoma cells with a tumor-driving ALK mutation induced cell death. Conversely, MES cells did not express either mutant or wild-type ALK and were resistant to ALKi, and MES cells formed tumors that progressed under ALKi therapy. In assessing the role of MES cells in relapse development, TRAIL was identified to specifically induce apoptosis in MES cells and to suppress MES tumor growth. Addition of TRAIL to ALKi treatment of neuroblastoma xenografts delayed relapses in a subset of the animals, suggesting a role for MES cells in relapse formation. While ADRN cells resembled normal embryonal neuroblasts, MES cells resembled immature precursor cells, which also lacked ALK expression. Resistance to targeted drugs can therefore be an intrinsic property of immature cancer cells based on their resemblance to developmental precursors. SIGNIFICANCE: In neuroblastoma, mesenchymal tumor cells lack expression of the tumor-driving ALK oncogene and are resistant to ALKi, but dual treatment with ALKi and mesenchymal cell-targeting TRAIL delays tumor relapse.
Insights
Immature mesenchymal (MES) neuroblastoma cells resist anaplastic lymphoma kinase inhibitors (ALKi). Combining ALKi with TRAIL therapy effectively targets MES cells and delays neuroblastoma relapse.
Area of Science:
- Oncology
- Developmental Biology
- Cancer Therapeutics
Background:
- Cancer therapy resistance is a major clinical challenge, often linked to immature tumor cell populations.
- Neuroblastoma cells exhibit plasticity, differentiating into adrenergic (ADRN) or immature mesenchymal (MES) states.
- MES cells display increased resistance to chemotherapy and harbor distinct epigenetic and transcriptional profiles compared to ADRN cells.
Purpose of the Study:
- To investigate the response of immature mesenchymal (MES) neuroblastoma cells to targeted therapies, specifically anaplastic lymphoma kinase inhibitors (ALKi).
- To evaluate the role of MES cells in neuroblastoma relapse and assess potential therapeutic strategies targeting these cells.
- To understand the intrinsic mechanisms of drug resistance in immature cancer cells.
Main Methods:
- Analysis of MES cell response to targeted drugs, including ALKi.
- Assessment of anaplastic lymphoma kinase (ALK) expression in both ADRN and MES neuroblastoma cells.
- In vivo studies using neuroblastoma xenografts treated with ALKi, TRAIL, or combination therapy to evaluate tumor progression and relapse dynamics.
Main Results:
- MES neuroblastoma cells lack both wild-type and mutant anaplastic lymphoma kinase (ALK) expression, rendering them resistant to ALKi.
- MES cells formed tumors that progressed under ALKi treatment, highlighting their role in therapeutic failure.
- TRAIL specifically induced apoptosis in MES cells and suppressed their tumor growth.
- Combination therapy with ALKi and TRAIL delayed relapse in a subset of neuroblastoma xenograft models.
Conclusions:
- Therapeutic resistance in neuroblastoma can be an intrinsic property of immature MES cells due to their lack of targetable oncogenes like ALK.
- Targeting MES cells with agents like TRAIL, in combination with ALKi, offers a promising strategy to overcome resistance and delay tumor relapse.
- The resemblance of MES cells to developmental precursor cells may explain their inherent resistance to targeted therapies.
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