TY - JOUR
T1 - Mesenchymal-Type Neuroblastoma Cells Escape ALK Inhibitors
AU - Westerhout, Ellen M.
AU - Hamdi, Mohamed
AU - Stroeken, Peter
AU - Nowakowska, Natalia E.
AU - Lakeman, Arjan
AU - van Arkel, Jennemiek
AU - Hasselt, Nancy E.
AU - Bleijlevens, Boris
AU - Akogul, Nurdan
AU - Haneveld, Franciska
AU - Chan, Alvin
AU - van Sluis, Peter
AU - Zwijnenburg, Danny
AU - Volckmann, Richard
AU - van Noesel, Carel J. M.
AU - Adameyko, Igor
AU - van Groningen, Tim
AU - Koster, Jan
AU - Valentijn, Linda J.
AU - van Nes, Johan
AU - Versteeg, Rogier
N1 - Funding Information: We thank Dr. Sue Cohn for providing the NBLW cell line. This research was funded by grants from the Villa Joep Foundation (to E.M. Westerhout, P. Stroeken, N.E. Hasselt, and J. van Nes), the European Research Council (ERC; advanced grant no. 340735; supporting M. Hamdi, N. Akogul, and F. Haneveld), and NWO (EraCoSysMed 9003035006 to T. van Groningen). Publisher Copyright: © 2021 American Association for Cancer Research.
PY - 2022/2/1
Y1 - 2022/2/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85124056607&partnerID=8YFLogxK
U2 - https://doi.org/10.1158/0008-5472.CAN-21-1621
DO - https://doi.org/10.1158/0008-5472.CAN-21-1621
M3 - Article
C2 - 34853072
SN - 0008-5472
VL - 82
SP - 484
EP - 496
JO - Cancer research
JF - Cancer research
IS - 3
ER -