Mohlin, SofieHansson, KarinRadke, KatarzynaMartinez, SoniaBlanco-Aparicio, CarmenGarcia-Ruiz, CristianWelinder, CharlotteEsfandyari, JavanshirO'Neill, MichaelPastor Fernandez, Joaquinvon Stedingk, KristofferBexell, Daniel2019-08-122019-08-122019-08EMBO Mol Med. 2019 ;11(8):e100581757-4676http://hdl.handle.net/20.500.12105/8209The 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.engVoRhttp://creativecommons.org/licenses/by-nc-sa/4.0/IBL-302PI3Kcisplatinmultikinase inhibitionneuroblastomaAtribución-NoComercial-CompartirIgual 4.0 Internacional31310053118e1005810.15252/emmm.2018100581757-4684EMBO molecular medicineopen access