Introduction
Genetic aberrations of ALK are associated with a poor event-free survival in neuroblastoma. In particular, ALK F1174L mutations are enriched within MYCN-amplified tumours and together are associated with an ultra-poor risk neuroblastoma subtype. We have previously shown in our preclinical mouse model of ALKF1174L/MYCN-driven neuroblastoma that the first generation ALK inhibitor crizotinib is unable to effectively treat the disease as single agent. This inadequacy was subsequently confirmed in a Phase I/II clinical study of crizotinib in patients. Thus, alternative therapeutic strategies must be found. We present here a study of two next generation compounds, LDK378 (Novartis) and PF-06463922 (Pfizer), using the Th-ALKF1174L/MYCN mouse model.
Methods
LDK378 and PF-06463922 were compared to crizotinib using in vitro assays. Subsequently pharmacodynamic studies were performed in the Th-ALKF1174L/MYCN mouse model and the phosphorylation status of ALK was compared using a mesoscale scale technology ELISA platform.
Results
PF-06463922 was found to be the superior compound in kinase assays and upon treatment of cell lines. In the transgenic Th-ALKF1174L/MYCN model PF-06463922 treatment resulted in tumour regression in all animals treated, associated with significant dephosphorylation of ALK according to ELISA and reduction in total MYCN upon immunoblotting. LDK378 treatment resulted in a variable and inadequate tumour response.
Discussion
PF-06463922 is a bona fide, potent, ALK inhibitor that should be considered as targeted therapy for children with neuroblastomas harbouring the ALK F1174L mutation, in preference to crizotinib and LDK378.