Anti-tumor effects of PIM/PI3K/mTOR triple kinase inhibitor IBL-302 in neuroblastoma
(2019) In EMBO Molecular Medicine 11(8).- 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... (More)
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.
(Less)
- author
- organization
- publishing date
- 2019-08-01
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- cisplatin, IBL-302, multikinase inhibition, neuroblastoma, PI3K
- in
- EMBO Molecular Medicine
- volume
- 11
- issue
- 8
- article number
- e10058
- publisher
- Wiley-Blackwell
- external identifiers
-
- pmid:31310053
- scopus:85069812158
- ISSN
- 1757-4676
- DOI
- 10.15252/emmm.201810058
- language
- English
- LU publication?
- yes
- id
- 49916c5f-7063-4ca0-9416-a9efb51a181b
- date added to LUP
- 2019-08-26 09:05:52
- date last changed
- 2024-01-16 08:50:26
@article{49916c5f-7063-4ca0-9416-a9efb51a181b, abstract = {{<p>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.</p>}}, author = {{Mohlin, Sofie and Hansson, Karin and Radke, Katarzyna and Martinez, Sonia and Blanco-Apiricio, Carmen and Garcia-Ruiz, Cristian and Welinder, Charlotte and Esfandyari, Javanshir and O'Neill, Michael and Pastor, Joaquin and von Stedingk, Kristoffer and Bexell, Daniel}}, issn = {{1757-4676}}, keywords = {{cisplatin; IBL-302; multikinase inhibition; neuroblastoma; PI3K}}, language = {{eng}}, month = {{08}}, number = {{8}}, publisher = {{Wiley-Blackwell}}, series = {{EMBO Molecular Medicine}}, title = {{Anti-tumor effects of PIM/PI3K/mTOR triple kinase inhibitor IBL-302 in neuroblastoma}}, url = {{http://dx.doi.org/10.15252/emmm.201810058}}, doi = {{10.15252/emmm.201810058}}, volume = {{11}}, year = {{2019}}, }