Zhang L, Wu B, and Baruchel S from the New Agent and Innovative Therapy Program, and Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Canada have just published in Translational Oncology a preclinical paper entitled : Oral Metronomic Topotecan Sensitizes Crizotinib Antitumor Activity in ALKF1174L Drug-Resistant Neuroblastoma Preclinical Models

ALK-inhibitor crizotinib is effective in the treatment of ALK-mutated neuroblastoma, but crizotinib resistance is frequently observed in patients. The authors aimed to overcome crizotinib resistance by combining with the MEK inhibitor trametinib or metronomic topotecan A panel of neuroblastoma cell lines carrying various ALK genetic aberrations was selected to evaluate the therapeutic efficacy on cell proliferation in vitro. Downstream signals of ALK activation, including phosphorylation of ERK1/2, Akt as well as HIF-1α expression were evaluated under normoxic and hypoxic conditions. Tumor growth inhibition was further evaluated in NOD/SCID xenograft mouse models.

All NBL cell lines responded to crizotinib treatment at ED50 levels, ranging from 0.25 to 5.58 μM. ALK-mutated cell lines SH-SY5Y, KELLY, LAN-5, and CHLA-20 were more sensitive than ALK wild-type cell lines. Under hypoxic conditions, all NBL cell lines showed marked decrease of ED50s as compared to normoxia. Interstingly, combined treatment with crizotinib and LDM topotecan demonstrated a synergistic effect in ALKF1174L-mutated SH-SY5Y cells in vitro. Furthermore, in vivo, while single-agent crizotinib showed limited antitumor activity in several xenograft models; the combination of crizotinib with metronomic topotecan, significantly delayed tumor development .

CONCLUSION : Oral metronomic topotecan reversed crizotinib drug resistance in the ALK-mutated neuroblastoma preclinical model.

the free full text of the paper is available here