The oral KIF11 inhibitor 4SC‐205 exhibits antitumor activity and potentiates standard and targeted therapies in primary and metastatic neuroblastoma models

Dear Editor, Neuroblastoma remains incurable for most patients with high-risk disease.1 Perturbation of transcription factors (MYCN and PHOX2B), kinases (ALK, MEK), and cell cycle regulators (CDK4/6, CHECK1), among other factors, make neuroblastoma cells highly proliferative, which is associated wit...

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Published in:	Clinical and translational medicine Vol. 11; no. 10; pp. e533 - n/a
Main Authors:	Masanas, Marc, Masiá, Nuria, Suárez‐Cabrera, Leticia, Olivan, Mireia, Soriano, Aroa, Majem, Blanca, Devis‐Jauregui, Laura, Burgos‐Panadero, Rebeca, Jiménez, Carlos, Rodriguez‐Sodupe, Pau, Boloix, Ariadna, Toledano, Ignasi, Guillén, Gabriela, Navarro, Alexandra, Llobet‐Navas, David, Villanueva, Alberto, Sánchez de Toledo, Josep, Roma, Josep, Noguera, Rosa, Moreno, Lucas, Krauss, Rolf, Gallego, Soledad, Santamaria, Anna, Segura, Miguel F.
Format:	Journal Article
Language:	English
Published:	United States John Wiley & Sons, Inc 01-10-2021 John Wiley and Sons Inc Wiley
Subjects:	Administration, Oral Animals Antineoplastic Agents - administration & dosage Antineoplastic Agents - pharmacology Cancer therapies Cell cycle Cell growth Cell Line, Tumor Chemotherapy Clinical trials Conflicts of interest Disease Models, Animal Humans Kinases Kinesins - antagonists & inhibitors Laboratory animals Letter to Editor Metastasis Mice Neuroblastoma Neuroblastoma - drug therapy Neuroblastoma - pathology Neuroblastoma - secondary Patients Phosphorylation Proteins Tumors
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Summary:	Dear Editor, Neuroblastoma remains incurable for most patients with high-risk disease.1 Perturbation of transcription factors (MYCN and PHOX2B), kinases (ALK, MEK), and cell cycle regulators (CDK4/6, CHECK1), among other factors, make neuroblastoma cells highly proliferative, which is associated with poor patient outcomes.2,3 To circumvent the limitations of the classical microtubule poisons such as vinca alcaloyds used in the treatment of neuroblastoma,1 we sought to explore alternative mitotic regulators as new therapeutic targets for high-risk neuroblastoma patients. SEE PDF] According to functional genomics, neuroblastoma cells seem to be one of the cell types that are more dependent on the expression of KIF11 for survival being particularly sensitive to its pharmacological inhibition.5 Concurring with these observations, the silencing of KIF11 caused a reduction in cell viability (Figure S3A-C) and a 3–4 fold reduction in the growth of established neuroblastoma subcutaneous xenografts (Figure 2A–C and S3D-R). Neuroblastoma cells treated with 4SC-205 (Figure 2E; Table S5) displayed all the expected phenotypic features resulting from KIF11 inhibition such as the inability to form bipolar spindles (Figures 2F and S4A), cell cycle arrest during mitosis (Figure S4B-H), and induction of apoptosis (Figure S5), thereby confirming the high KIF11 specificity of this compound. Pediatric precision medicine programs have discovered a small number of recurrent alterations such as ALK activating mutations or hyperactivation of the ERK Pathway,9,10 which constitute the basis for the development of targeted therapies against high-risk neuroblastoma tumors. [...]we combined 4SC-205 with two ALK inhibitors (ceritinib and lorlatinib) or with the MEK1/2 inhibitor selumetinib.
Bibliography:	Funding information The financial support for this research was provided by Instituto de Salud Calos III (PI20/00530 to Miguel F. Segura; PI20/01107 to Rosa Noguera; PI17/02248 and CPII18/00027 to Anna Santamaria; PI19/01320 to Alberto Villanueva); Ministerio de Educación, Cultura y Deporte (Grant no. FPU16/01099 to Marc Masanas). This work was also supported by the Asociación NEN (Nico contra el cancer infantil 2017–PVR00157). SourceType-Other Sources-1 ObjectType-Article-2 content type line 63 ObjectType-Correspondence-1
ISSN:	2001-1326 2001-1326
DOI:	10.1002/ctm2.533