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ALK has been identified as a novel therapeutic target in neuroblastoma (NB), but resistance to ALK inhibitors (such as crizotinib) is well recognized. We recently published that the crizotinib sensitivity in NB cells strongly correlates with the crizotinib-ALK binding, and β-catenin effectively hinders this interaction and confers crizotinib resistance. Here, we asked if these observations hold true for the stem-like cells in NB cells, which were purified based on their responsiveness to a Sox2 reporter. Compared to bulk, reporter unresponsive (RU) cells, reporter responsive (RR) cells had significantly higher neurosphere formation ability, expression of CD133/nestin and chemo-resistance. Using the cellular thermal shift assay, we found that RR cells exhibited significantly weaker crizotinib-ALK binding and higher crizotinib resistance than RU cells. The suboptimal crizotinib-ALK binding in RR cells can be attributed to their high β-catenin expression, since siRNA knockdown of β-catenin restored the crizotinib-ALK binding and lowered the crizotinib resistance to the level of RU cells. Enforced expression of β-catenin in RU cells resulted in the opposite effects. To conclude, high expression of β-catenin in the stem-like NB cells contributes to their crizotinib resistance. Combining β-catenin inhibitors and ALK inhibitors may be useful in treating NB patients.
Pubmed ID: 29203817
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View all literature mentionsCell line SK-N-SH is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line SK-N-SH is a Cancer cell line with a species of origin Homo sapiens (Human)
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