AVJ16 inhibits lung carcinoma by targeting IGF2BP1.

Abstract

IGF2BP1 is an oncofoetal RNA binding protein (RBP) expressed in many tumors. Interest has focused of late on the role of RBPs in cancer, although their mechanism of action is not always well understood. Using a newly described small molecule inhibitor of IGF2BP1, termed AVJ16, we have analyzed the effects of this inhibition on RNA binding, RNA expression, and protein expression. AVJ16 treatment downregulates RNAs encoding members of several pro-oncogenic signaling pathways, including Hedgehog, Wnt, and PI3K-Akt, and there is a strong correlation between IGF2BP1 RNA binding, RNA expression, and protein expression. At the cellular level, colony formation, invasion, and spheroid growth are all strongly reduced by exposure to AVJ16, while apoptosis and cell death are enhanced. All of these effects are limited to cells expressing IGF2BP1. In syngeneic LUAD xenografts in mice, IP injection of AVJ16 prevents tumor growth, and incubation with AVJ16 induces cell death in human organoids derived from IGF2BP1-expressing LUADs but not from healthy lung tissue. These results demonstrate that AVJ16 is a promising candidate for targeted therapy directed against tumors expressing IGF2BP1. Please use revised graphical abstract that I uploaded - we found a slight mistake in the original one.