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

Abstract

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 (dnULK1) 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. .

ULK1 inhibition as a targeted therapeutic strategy for FLT3-ITD-mutated acute myeloid leukemia

“…Increasing evidence suggests that dysregulated autophagy is a hallmark of malignant disorders and plays complex roles in the tumorigenesis and progression of cancers and their resistance to treatment, in a contextdependent manner [10,11,31]. The diverse functions of numerous autophagy-related proteins in cancer have been extensively evaluated [31,34].…”

“…Autophagy is a cell-protective and degradative process that recycles damaged and long-lived cellular components [9]. Autophagy has opposing roles in cancers, depending on the context, oncogenesis, biological features, treatment, and progression [10][11][12]. In certain cases, autophagy acts primarily as a tumor-suppressive mechanism by maintaining genomic integrity and preventing proliferation and inflammation [12].…”

Comparison of Stage 4 and Stage 4s Neuroblastoma Identifies Autophagy-Related Gene and LncRNA Signatures Associated With Prognosis

“…In recent years, autophagy has been found to play important roles in tumor development and progression (21,22) and is also involved in NB (23)(24)(25)(26). The association between autophagy and spontaneous regression of NB is unknown.…”

Conservation of structure, function and inhibitor binding in UNC-51-like kinase 1 and 2 (ULK1/2)

“…With essential roles in diseases [36][37][38][39][40] , ULK1 has been identified as an attractive target for inhibition of the autophagy pathway. Crystal structures of ULK1 provide insights into the druggable pockets of this kinase 41 , leading to the development of several inhibitors, including SBI-0206965 42 , MRT67307, MRT68921 43 and recently ULK-101 44 .…”