Examination of a new putative neuroblastoma inhibitor.

A newly report published in the journal Disease Models & Mechanisms from the Hallberg-Palmer research groups, working together with the Chesler lab at the Institute of Cancer Research, U.K. shows that a new ALK inhibitor, Lorlatinib (PF-06463922), shows remarkable pre-clinical efficacy in treatment of ALK-positive  neuroblasoma.  Lorlatinib was developed from the first ALK inhibitor, crizotinib (Xalkori), which was FDA approved for use in ALK-positive non-small-cell-lung-cancer 2011.


In neuroblastoma, activating mutations in the ALK kinase domain are typically refractory to crizotinib treatment, highlighting the need for more potent inhibitors. The next-generation ALK inhibitor Lorlatinib might be the answer; and in this work the research groups examined lorlatinib activity in ALK-driven neuroblastoma models in vitro and in vivo.


Lorlatinib has increased activity towards ALK mutants prevalent in neuroblastoma examined in both in vitro kinase assays and cell-based experiments examining ALK mutations.  In contrast to crizotinib, single agent administration of lorlatinib causes a dramatic tumor inhibition in mouse models of high-risk neuroblastoma. Taken together, the research groups show that lorlatinib is a potent inhibitor of crizotinib-resistant ALK mutations, and highlight an important new treatment option for neuroblastoma patients.3LCS ALK Lee et al S1281G mutation R and C spine with SHELL surface C-helix

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