PI3K/PTEN/Akt pathway status affects the sensitivity of high-grade glioma cell cultures to the insulin-like growth factor-1 receptor inhibitor NVP-AEW541.
IGF-1 receptor signaling contributes to the growth of many solid tumors, including glioblastoma. This study analyzed the sensitivity of 8 glioblastoma cultures to the IGF-1 receptor inhibitor NVP-AEW541. Growth reduction, caused by a combination of antiproliferative and proapoptotic effects, varied between 20% and 100%. Growth-inhibitory effects of IGF-1 receptor siRNA were also demonstrated in 2 of the cultures. Activating mutations in PIK3CA were found in 2 cultures, and 2 other cultures displayed ligand-independent Akt phosphorylation. Growth inhibition was significantly reduced in cultures with PIK3CA mutations or ligand-independent Akt phosphorylation. PTEN siRNA experiments supported the notion that the status of the PI3K/PTEN/Akt pathway is involved in determining NVP-AEW541 sensitivity. Combination treatments with either PI3 kinase or mTOR inhibitors together with NVP-AEW541 were performed. These experiments demonstrated the effects of NVP-AEW541 in cells not responding to mono-treatment with the IGF-1 receptor inhibitor, when used together with either of the 2 other inhibitors. Together, the studies support continued clinical development of IGF-1 receptor antagonists for glioblastomas and identify links between PI3K/PTEN/Akt status and sensitivity to mono-treatment with NVP-AEW541. Furthermore, the studies suggest that NVP-AEW541 is also active together with PI3 kinase and mTOR inhibitors in cultures with a dysregulated PI3K/PTEN/Akt pathway. These studies should assist in future clinical development of IGF-1 receptor antagonists for glioblastoma and other tumors.
Hägerstrand
Daniel
D
Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska, Stockholm, Sweden.
Lindh
Maja Bradic
MB
Peña
Cristina
C
Garcia-Echeverria
Carlos
C
Nistér
Monica
M
Hofmann
Francesco
F
Ostman
Arne
A
D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005910:Glioma / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D034741:RNA, Small Interfering; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
D000970:Antineoplastic Agents; C501177:NVP-AEW541; D011743:Pyrimidines; D011758:Pyrroles; D034741:RNA, Small Interfering; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase