Specific apoptosis induction by the dual PI3K/mTor inhibitor NVP-BEZ235 in HER2 amplified and PIK3CA mutant breast cancer cells.
NVP-BEZ235 is a dual PI3K/mTOR inhibitor currently in phase I clinical trials. We profiled this compound against a panel of breast tumor cell lines to identify the patient populations that would benefit from such treatment. In this setting, NVP-BEZ235 selectively induced cell death in cell lines presenting either HER2 amplification and/or PIK3CA mutation, but not in cell lines with PTEN loss of function or KRAS mutations, for which resistance could be attributed, in part to ERK pathway activity. An in depth analysis of death markers revealed that the cell death observed upon NVP-BEZ235 treatment could be recapitulated with other PI3K inhibitors and that this event is linked to active PARP cleavage indicative of an apoptotic process. Moreover, the effect seemed to be partly independent of the caspase-9 executioner and mitochondrial activated caspases, suggesting an alternate route for apoptosis induction by PI3K inhibitors. Overall, this study will provide guidance for patient stratification for forthcoming breast cancer phase II trials for NVP-BEZ235.
Brachmann
Saskia M
SM
Novartis Institutes for Biomedical Research, Oncology Disease Area, CH-4002 Basel, Switzerland.
Hofmann
Irmgard
I
Schnell
Christian
C
Fritsch
Christine
C
Wee
Susan
S
Lane
Heidi
H
Wang
Shaowen
S
Garcia-Echeverria
Carlos
C
Maira
Sauveur-Michel
SM
D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005784:Gene Amplification; D018734:Genes, erbB-2 / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000187:drug effects*; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects*; D011804:Quinolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases
D053453:Caspase 9; D058534:Class I Phosphatidylinositol 3-Kinases; D004791:Enzyme Inhibitors; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases; D011804:Quinolines; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C484760:PIK3CA protein, human; C494929:PTEN protein, human; C506433:CASP9 protein, human; C531198:dactolisib