Open AccessAnti‐tumor effects of PIM / PI 3K/ mTOR triple kinase inhibitor IBL ‐302 in neuroblastoma
Author(s) -
Mohlin Sofie,
Hansson Karin,
Radke Katarzyna,
Martinez Sonia,
BlancoApiricio Carmen,
GarciaRuiz Cristian,
Welinder Charlotte,
Esfandyari Javanshir,
O'Neill Michael,
Pastor Joaquin,
Stedingk Kristoffer,
Bexell Daniel
Publication year - 2019
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201810058
Subject(s) - cancer , library science , medicine , computer science
Abstract The PI 3K pathway is a major driver of cancer progression. However, clinical resistance to PI 3K inhibition is common. IBL ‐302 is a novel highly specific triple PIM , PI 3K, and mTOR inhibitor. Screening IBL ‐302 in over 700 cell lines representing 47 tumor types identified neuroblastoma as a strong candidate for PIM / PI 3K/ mTOR inhibition. IBL ‐302 was more effective than single PI 3K 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 / PI 3K/ mTOR inhibition has the potential to improve clinical outcomes and reduce severe late effects in children with high‐risk neuroblastoma.