Helmholtz Gemeinschaft

Search
Browse
Statistics
Feeds

Mutations in ALK signaling pathways conferring resistance to ALK inhibitor treatment lead to collateral vulnerabilities in neuroblastoma cells

[thumbnail of Original Article]
Preview
PDF (Original Article) - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
3MB
[thumbnail of Supplementary Information] Other (Supplementary Information)
3MB

Item Type:Article
Title:Mutations in ALK signaling pathways conferring resistance to ALK inhibitor treatment lead to collateral vulnerabilities in neuroblastoma cells
Creators Name:Berlak, M., Tucker, E., Dorel, M., Winkler, A., McGearey, A., Rodriguez-Fos, E., da Costa, B.M., Barker, K., Fyle, E., Calton, E., Eising, S., Ober, K., Hughes, D., Koutroumanidou, E., Carter, P., Stankunaite, R., Proszek, P., Jain, N., Rosswog, C., Dorado-Garcia, H., Molenaar, J.J., Hubank, M., Barone, G., Anderson, J., Lang, P., Deubzer, H.E., Künkele, A., Fischer, M., Eggert, A., Kloft, C., Henssen, A.G., Boettcher, M., Hertwig, F., Blüthgen, N., Chesler, L. and Schulte, J.H.
Abstract:BACKGROUND: Development of resistance to targeted therapies has tempered initial optimism that precision oncology would improve poor outcomes for cancer patients. Resistance mechanisms, however, can also confer new resistance-specific vulnerabilities, termed collateral sensitivities. Here we investigated anaplastic lymphoma kinase (ALK) inhibitor resistance in neuroblastoma, a childhood cancer frequently affected by activating ALK alterations. METHODS: Genome-wide forward genetic CRISPR-Cas9 based screens were performed to identify genes associated with ALK inhibitor resistance in neuroblastoma cell lines. Furthermore, the neuroblastoma cell line NBLW-R was rendered resistant by continuous exposure to ALK inhibitors. Genes identified to be associated with ALK inhibitor resistance were further investigated by generating suitable cell line models. In addition, tumor and liquid biopsy samples of four patients with ALK-mutated neuroblastomas before ALK inhibitor treatment and during tumor progression under treatment were genomically profiled. RESULTS: Both genome-wide CRISPR-Cas9-based screens and preclinical spontaneous ALKi resistance models identified NF1 loss and activating NRAS(Q61K) mutations to confer resistance to chemically diverse ALKi. Moreover, human neuroblastomas recurrently developed de novo loss of NF1 and activating RAS mutations after ALKi treatment, leading to therapy resistance. Pathway-specific perturbations confirmed that NF1 loss and activating RAS mutations lead to RAS-MAPK signaling even in the presence of ALKi. Intriguingly, NF1 loss rendered neuroblastoma cells hypersensitive to MEK inhibition. CONCLUSIONS: Our results provide a clinically relevant mechanistic model of ALKi resistance in neuroblastoma and highlight new clinically actionable collateral sensitivities in resistant cells.
Keywords:Anaplastic Lymphoma Kinase, Mutation, Neuroblastoma, Precision Medicine, Protein Kinase Inhibitors, Signal Transduction, Tumor Cell Line
Source:Molecular Cancer
ISSN:1476-4598
Publisher:BioMed Central
Volume:21
Number:1
Page Range:126
Date:10 June 2022
Official Publication:https://doi.org/10.1186/s12943-022-01583-z
PubMed:View item in PubMed

Repository Staff Only: item control page

Downloads

Downloads per month over past year

Open Access
MDC Library