Anti‐tumor effects of PIM/PI3K/mTOR triple kinase inhibitor IBL‐302 in neuroblastoma

• Main Authors: Sofie Mohlin, Karin Hansson, Katarzyna Radke, Sonia Martinez, Carmen Blanco‐Apiricio, Cristian Garcia‐Ruiz, Charlotte Welinder, Javanshir Esfandyari, Michael O'Neill, Joaquin Pastor, Kristoffer vonStedingk, Daniel Bexell
• Format: Article
• Language: English
• Published: Wiley 2019-08-01
• Series: EMBO Molecular Medicine
• Subjects: cisplatin; IBL‐302; multikinase inhibition; neuroblastoma; PI3K
• Online Access: https://doi.org/10.15252/emmm.201810058

Abstract The PI3K pathway is a major driver of cancer progression. However, clinical resistance to PI3K inhibition is common. IBL‐302 is a novel highly specific triple PIM, PI3K, and mTOR inhibitor. Screening IBL‐302 in over 700 cell lines representing 47 tumor types identified neuroblastoma as a strong candidate for PIM/PI3K/mTOR inhibition. IBL‐302 was more effective than single PI3K inhibition in vitro, and IBL‐302 treatment of neuroblastoma patient‐derived xenograft (PDX) cells induced apoptosis, differentiated tumor cells, and decreased N‐Myc protein levels. IBL‐302 further enhanced the effect of the common cytotoxic chemotherapies cisplatin, doxorubicin, and etoposide. Global genome, proteome, and phospho‐proteome analyses identified crucial biological processes, including cell motility and apoptosis, targeted by IBL‐302 treatment. While IBL‐302 treatment alone reduced tumor growth in vivo, combination therapy with low‐dose cisplatin inhibited neuroblastoma PDX growth. Complementing conventional chemotherapy treatment with PIM/PI3K/mTOR inhibition has the potential to improve clinical outcomes and reduce severe late effects in children with high‐risk neuroblastoma.