Targeted Inhibition of ULK1 Promotes Apoptosis and Suppresses Tumor Growth and Metastasis in Neuroblastoma

Mol Cancer Ther. 2018 Nov;17(11):2365-2376. doi: 10.1158/1535-7163.MCT-18-0176. Epub 2018 Aug 30.


Neuroblastoma is the most common extracranial solid malignancy in the pediatric population, accounting for over 9% of all cancer-related deaths in children. Autophagy is a cell self-protective mechanism that promotes tumor cell growth and survival, making it an attractive target for treating cancer. However, the role of autophagy in neuroblastoma tumor growth and metastasis is largely undefined. Here we demonstrate that targeted inhibition of an essential autophagy kinase, unc-51 like autophagy kinase 1 (ULK1), with a recently developed small-molecule inhibitor of ULK1, SBI-0206965, significantly reduces cell growth and promotes apoptosis in SK-N-AS, SH-SY5Y, and SK-N-DZ neuroblastoma cell lines. Furthermore, inhibition of ULK1 by a dominant-negative mutant of ULK1 (dnULK1K46N) significantly reduces growth and metastatic disease and prolongs survival of mice bearing SK-N-AS xenograft tumors. We also show that SBI-0206965 sensitizes SK-N-AS cells to TRAIL treatment, but not to mTOR inhibitors (INK128, Torin1) or topoisomerase inhibitors (doxorubicin, topotecan). Collectively, these findings demonstrate that ULK1 is a viable drug target and suggest that inhibitors of ULK1 may provide a novel therapeutic option for the treatment of neuroblastoma. Mol Cancer Ther; 17(11); 2365-76. ©2018 AACR.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis* / drug effects
  • Autophagy-Related Protein-1 Homolog / antagonists & inhibitors*
  • Autophagy-Related Protein-1 Homolog / metabolism
  • Benzamides / chemistry
  • Benzamides / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasm Metastasis
  • Neuroblastoma / enzymology*
  • Neuroblastoma / pathology*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism
  • Topoisomerase Inhibitors / pharmacology
  • Xenograft Model Antitumor Assays


  • Benzamides
  • Intracellular Signaling Peptides and Proteins
  • Pyrimidines
  • SBI-0206965
  • TNF-Related Apoptosis-Inducing Ligand
  • Topoisomerase Inhibitors
  • Autophagy-Related Protein-1 Homolog
  • TOR Serine-Threonine Kinases
  • ULK1 protein, human