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

In this article, they show using a panel of neuroblastoma cell lines carrying various ALK genetic aberrations that metronomic topotecan can reverse resistance to crizotinib.

While all NBL cell lines responded to crizotinib treatment, variable ED50 levels, ranging from 0.25 to 5.58 μM were necessary. Interestingly, ALK-mutated cell lines SH-SY5Y, KELLY, LAN-5, and CHLA-20 were more sensitive than ALK wild-type cell lines. In addition, the authors showed that under hypoxic conditions, all NBL cell lines showed marked decrease of ED50s when compared to normoxia except for KELLY cells. Combined treatment with crizotinib and LDM topotecan demonstrated a synergistic effect in ALKF1174L-mutated SH-SY5Y cells. Moreover, in vivo, single-agent crizotinib showed only limited antitumor activity in ALKF1174L-mutated SH-SY5Y and KELLY xenograft models. However, when combined with topotecan, significantly delayed tumor development was achieved in both SH-SY5Y and KELLY tumor models. Therefore, oral metronomic topotecan reversed crizotinib drug resistance in the ALKF1174L-mutated neuroblastoma preclinical model further confirming the potential of combining metronomic chemotherapy with targeted therapies.