Alectinib, an Anaplastic Lymphoma Kinase Inhibitor, Abolishes ALK Activity and Growth in ALK-Positive Neuroblastoma Cells

Alam, Muhammad Wasi; Borenäs, Marcus; Lind, Dan E.; Cervantes-Madrid, Diana; Umapathy, Ganesh; Palmer, Ruth; Hållberg, Bengt

doi:10.3389/fonc.2019.00579

Cited by 25 publications

(23 citation statements)

References 60 publications

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“…Encouraging therapeutic outcomes have been observed in several clinical studies [11]. These inhibitors suppress cell growth by inhibiting signaling pathways downstream of ALK [32][33][34][35]. Our study shows that three ALK inhibitors suppress proliferation of SH-SY5Y and H2228 cells ( Figures 1B and 6A).…”

Section: Discussionsupporting

confidence: 62%

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ALK Inhibitors-Induced M Phase Delay Contributes to the Suppression of Cell Proliferation

Munira

Yuki

Saito

et al. 2020

Cancers

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Anaplastic lymphoma kinase (ALK), a receptor-type tyrosine kinase, is involved in the pathogenesis of several cancers. ALK has been targeted with small molecule inhibitors for the treatment of different cancers, but absolute success remains elusive. In the present study, the effects of ALK inhibitors on M phase progression were evaluated. Crizotinib, ceritinib, and TAE684 suppressed proliferation of neuroblastoma SH-SY5Y cells in a concentration-dependent manner. At approximate IC50 concentrations, these inhibitors caused misorientation of spindles, misalignment of chromosomes and reduction in autophosphorylation. Similarly, knockdown of ALK caused M phase delay, which was rescued by re-expression of ALK. Time-lapse imaging revealed that anaphase onset was delayed. The monopolar spindle 1 (MPS1) inhibitor, AZ3146, and MAD2 knockdown led to a release from inhibitor-induced M phase delay, suggesting that spindle assembly checkpoint may be activated in ALK-inhibited cells. H2228 human lung carcinoma cells that express EML4-ALK fusion showed M phase delay in the presence of TAE684 at about IC50 concentrations. These results suggest that ALK plays a role in M phase regulation and ALK inhibition may contribute to the suppression of cell proliferation in ALK-expressing cancer cells.

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Section: Discussionsupporting

confidence: 62%

“…ALK plays an important role in tumorigenesis, and it is expressed at high levels in some types of tumor. In particular, signaling mediated by ALK is essential for cancer cell proliferation and survival [32][33][34][35]. Conversely, normal cells express no or low levels of ALK when ALK is expressed [10,36].…”

Section: Discussionmentioning

confidence: 99%

ALK Inhibitors-Induced M Phase Delay Contributes to the Suppression of Cell Proliferation

Munira

Yuki

Saito

et al. 2020

Cancers

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“…The first clinical study in NB employed the first‐generation inhibitor crizotinib (Mosse et al , 2013). Since then, a range of ALK TKIs including ceritinib, lorlatinib, brigatinib, alectinib and repotrectinib have been explored in a preclinical NB setting as well as in several published clinical case reports (Heukamp et al , 2012; Guan et al , 2016; Infarinato et al , 2016; Iyer et al , 2016; Siaw et al , 2016; Guan et al , 2018; Alam et al , 2019; Cervantes‐Madrid et al , 2019). While ALK mutations are identified in less than 10% of primary NB cases, this number is now appreciated to be far higher in the relapsed NB population (Schleiermacher et al , 2014; Eleveld et al , 2015).…”

Section: Discussionmentioning

confidence: 99%

ALK ligand ALKAL2 potentiates MYCN‐driven neuroblastoma in the absence of ALK mutation

et al. 2021

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High-risk neuroblastoma (NB) is responsible for a disproportionate number of childhood deaths due to cancer. One indicator of highrisk NB is amplification of the neural MYC (MYCN) oncogene, which is currently therapeutically intractable. Identification of anaplastic lymphoma kinase (ALK) as an NB oncogene raised the possibility of using ALK tyrosine kinase inhibitors (TKIs) in treatment of patients with activating ALK mutations. 8-10% of primary NB patients are ALK-positive, a figure that increases in the relapsed population. ALK is activated by the ALKAL2 ligand located on chromosome 2p, along with ALK and MYCN, in the "2p-gain" region associated with NB. Dysregulation of ALK ligand in NB has not been addressed, although one of the first oncogenes described was v-sis that shares > 90% homology with PDGF. Therefore, we tested whether ALKAL2 ligand could potentiate NB progression in the absence of ALK mutation. We show that ALKAL2 overexpression in mice drives ALK TKI-sensitive NB in the absence of ALK mutation, suggesting that additional NB patients, such as those exhibiting 2p-gain, may benefit from ALK TKI-based therapeutic intervention.

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“…Given these findings, as well as the reports of improved efficacy of response of murine Th-MYCN/Alk_F1178L tumors to combined ALK/RET TKI (crizotinib/vandetanib) treatment [ 37 ], it is worth considering exploration of TKIs that target both ALK and RET. One such example is alectinib, which was shown to effectively inhibit a range of ALK mutant variants in an NB setting, as well as to effectively inhibit oncogenic RET [ 59 , 60 ].…”

Section: Discussionmentioning

confidence: 99%

Loss of RET Promotes Mesenchymal Identity in Neuroblastoma Cells

Siaw

Gabre

Uçkun

et al. 2021

Cancers

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Aberrant activation of anaplastic lymphoma kinase (ALK) drives neuroblastoma (NB). Previous work identified the RET receptor tyrosine kinase (RTK) as a downstream target of ALK activity in NB models. We show here that ALK activation in response to ALKAL2 ligand results in the rapid phosphorylation of RET in NB cells, providing additional insight into the contribution of RET to the ALK-driven gene signature in NB. To further address the role of RET in NB, RET knockout (KO) SK-N-AS cells were generated by CRISPR/Cas9 genome engineering. Gene expression analysis of RET KO NB cells identified a reprogramming of NB cells to a mesenchymal (MES) phenotype that was characterized by increased migration and upregulation of the AXL and MNNG HOS transforming gene (MET) RTKs, as well as integrins and extracellular matrix components. Strikingly, the upregulation of AXL in the absence of RET reflects the development timeline observed in the neural crest as progenitor cells undergo differentiation during embryonic development. Together, these findings suggest that a MES phenotype is promoted in mesenchymal NB cells in the absence of RET, reflective of a less differentiated developmental status.

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Alectinib, an Anaplastic Lymphoma Kinase Inhibitor, Abolishes ALK Activity and Growth in ALK-Positive Neuroblastoma Cells

Cited by 25 publications

References 60 publications

ALK Inhibitors-Induced M Phase Delay Contributes to the Suppression of Cell Proliferation

ALK Inhibitors-Induced M Phase Delay Contributes to the Suppression of Cell Proliferation

ALK ligand ALKAL2 potentiates MYCN‐driven neuroblastoma in the absence of ALK mutation

Loss of RET Promotes Mesenchymal Identity in Neuroblastoma Cells

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