Mesenchymal-Type Neuroblastoma Cells Escape ALK Inhibitors

Ellen M. Westerhout, Mohamed Hamdi, Peter Stroeken, Natalia E. Nowakowska, Arjan Lakeman, Jennemiek van Arkel, Nancy E. Hasselt, Boris Bleijlevens, Nurdan Akogul, Franciska Haneveld, Alvin Chan, Peter van Sluis, Danny Zwijnenburg, Richard Volckmann, Carel J. M. van Noesel, Igor Adameyko, Tim van Groningen, Jan Koster, Linda J. Valentijn, Johan van NesRogier Versteeg

Research output: Contribution to journalArticleAcademicpeer-review

9 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)484-496
Number of pages13
JournalCancer research
Volume82
Issue number3
DOIs
Publication statusPublished - 1 Feb 2022

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