日本語
 
Help Privacy Policy ポリシー/免責事項
  詳細検索ブラウズ

アイテム詳細

登録内容を編集ファイル形式で保存
一時保存へ追加
  タグ情報を表示リリース履歴を表示詳細要約

公開
学術論文

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

MPS-Authors
/persons/resource/persons261085

Dorel,  Mathurin
Gene Regulation and Systems Biology of Cancer (Marie-Laure Yaspo), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

External Resource
There are no locators available
Fulltext (restricted access)
There are currently no full texts shared for your IP range.
フルテキスト (公開)
付随資料 (公開)
There is no public supplementary material available
引用

Berlak, M., Tucker, E., Dorel, M., Winkler, A., McGearey, A., Rodriguez-Fos, E., Martins da Costa, B., 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., & Schulte, J. H. (2022). Mutations in ALK signaling pathways conferring resistance to ALK inhibitor treatment lead to collateral vulnerabilities in neuroblastoma cells. Molecular Cancer, 21:. doi:10.1186/s12943-022-01583-z.


引用: https://hdl.handle.net/21.11116/0000-000A-BB62-5
要旨
Background: Development of resistance to targeted therapies has tempered initial optimism that precision oncol‑
ogy 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 associ‑
ated 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 sam‑
ples 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 identi‑
fied NF1 loss and activating NRASQ61K 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, lead‑
ing 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 hypersensi‑
tive 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.