Targeting ALK and ERK5 is a new strategy for neuroblastoma treatment

 

Neuroblastoma is a complex malignant tumor that develops from neural crest and is responsible for about 15% of childhood death. Increased expression of MYCN gene, encoded a transcription factor MYCN, is related to neuroblastomas. Umapathy et al. found kinase ERK5 regulates Anaplastic lymphoma kinase (ALK) induced MYCN transcription and proliferation of neuroblastoma. The article was published on Science Signaling, recently.

 

ALK-targeted therapy is currently applied in the treatment of ALK-positive cancer, through using ALK inhibitors. However, the strategy shows insufficient for ALK-positive neuroblastoma patients. Researchers demonstrated that ALK-mediated ERK5 phosphorylation was requited both at MYCN gene expression and at transcriptional level in neuroblastoma cells. In addition, PI3K activity was important in regulation ALK-mediated ERK5 activation. By reducing the activities of ALK or ERK, or both, researchers found a significant decrease of meuroblastoma cell proliferation. However, the combination treatment was more effective then the single-agent treatments both in vitro and in vivo.

 

The results indicates that combination therapy of inhibiting ALK and ERK5 may be a novel strategy for ALK-positive neuroblastoma patients. Moreover, the new strategy may overcome unfavorable clinical trial of crizotinib monotherapy, which plays significant antitumo activity in ALK-positive cancer patients, except for those with neuroblastoma.

 

Reference:
Sci Signal. 2014 Oct 28;7(349):ra102.

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Cat.No.	Product Name	Information
S1068	Crizotinib	Crizotinib is a potent inhibitor of c-Met and ALK with IC50 of 11 nM and 24 nM in cell-based assays, respectively. It is also a potent ROS1 inhibitor with Ki value less than 0.025 nM. Crizotinib induces autophagy through inhibition of the STAT3 pathway in multiple lung cancer cell lines.
S7525	XMD8-92	XMD8-92 is a potent and selective dual inhibitor of big map kinase (BMK1, ERK5) and bromodomain-containing proteins (BRDs, BET) with Kd of 80 nM and 170 nM for ERK5 and BRD4(1), respectively.

Related Targets

ALK