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oai:repisalud.isciii.es:20.500.12105/82092024-11-29T19:22:28Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Mohlin, Sofie author Hansson, Karin author Radke, Katarzyna author Martinez, Sonia author Blanco-Aparicio, Carmen author Garcia-Ruiz, Cristian author Welinder, Charlotte author Esfandyari, Javanshir author O'Neill, Michael author Pastor Fernandez, Joaquin author von Stedingk, Kristoffer author Bexell, Daniel author 2019-08 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. EMBO Mol Med. 2019 ;11(8):e10058 10.15252/emmm.201810058 1757-4684 1757-4676 EMBO molecular medicine 31310053 http://hdl.handle.net/20.500.12105/8209 IBL-302 PI3K cisplatin multikinase inhibition neuroblastoma Anti-tumor effects of PIM/PI3K/mTOR triple kinase inhibitor IBL-302 in neuroblastoma