Wallis Nadav, Gershon Tehila, Shaaby Sojod, Oberman Froma, Grunewald Myriam, Duran Deborah, Singh Amandeep, Vainer Gilad, Spiegelman Vladimir S, Sharma Arun K, Yisraeli Joel K
Department of Developmental Biology and Cancer Research, Institute for Medical Research - Israel-Canada, Hebrew University Hadassah Medical School, Jerusalem, Israel.
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
Oncogene. 2025 Jul 8. doi: 10.1038/s41388-025-03449-2.
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.
IGF2BP1是一种在许多肿瘤中表达的癌胚RNA结合蛋白（RBP）。尽管RBP的作用机制并不总是被很好地理解，但近来人们的兴趣集中在其在癌症中的作用上。我们使用一种新描述的名为AVJ16的IGF2BP1小分子抑制剂，分析了这种抑制对RNA结合、RNA表达和蛋白质表达的影响。AVJ16处理下调了编码几种促癌信号通路成员的RNA，包括Hedgehog、Wnt和PI3K-Akt，并且IGF2BP1的RNA结合、RNA表达和蛋白质表达之间存在很强的相关性。在细胞水平上，暴露于AVJ16会强烈降低集落形成、侵袭和球体生长，同时增强细胞凋亡和细胞死亡。所有这些效应都仅限于表达IGF2BP1的细胞。在小鼠同基因肺腺癌异种移植模型中，腹腔注射AVJ16可阻止肿瘤生长，并且与AVJ16孵育可诱导源自表达IGF2BP1的肺腺癌的人器官样组织中的细胞死亡，但不能诱导源自健康肺组织的细胞死亡。这些结果表明，AVJ16是针对表达IGF2BP1的肿瘤进行靶向治疗的一个有前景的候选药物。请使用我上传的修订后的图形摘要——我们在原来的摘要中发现了一个小错误。
