Specific apoptosis induction by the dual PI3K/mTor inhibitor NVP-BEZ235 in HER2 amplified and PIK3CA mutant breast cancer cells

Saskia M Brachmann; Irmgard Hofmann; Christian Schnell; Christine Fritsch; Susan Wee; Heidi Lane; Shaowen Wang; Carlos Garcia-Echeverria; Sauveur-Michel Maira

doi:10.1073/pnas.0905152106

Specific apoptosis induction by the dual PI3K/mTor inhibitor NVP-BEZ235 in HER2 amplified and PIK3CA mutant breast cancer cells

Proc Natl Acad Sci U S A. 2009 Dec 29;106(52):22299-304. doi: 10.1073/pnas.0905152106. Epub 2009 Dec 10.

Authors

Saskia M Brachmann¹, Irmgard Hofmann, Christian Schnell, Christine Fritsch, Susan Wee, Heidi Lane, Shaowen Wang, Carlos Garcia-Echeverria, Sauveur-Michel Maira

Affiliation

¹ Novartis Institutes for Biomedical Research, Oncology Disease Area, CH-4002 Basel, Switzerland.

Abstract

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.

MeSH terms

Apoptosis / drug effects*
Apoptosis / genetics
Apoptosis / physiology
Breast Neoplasms / drug therapy*
Breast Neoplasms / genetics
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Caspase 9 / metabolism
Cell Line, Tumor
Class I Phosphatidylinositol 3-Kinases
Drug Resistance, Neoplasm / genetics
Drug Resistance, Neoplasm / physiology
Enzyme Inhibitors / pharmacology
Female
Gene Amplification
Genes, erbB-2* / drug effects
Humans
Imidazoles / pharmacology*
Intracellular Signaling Peptides and Proteins / drug effects*
Mutation
PTEN Phosphohydrolase / genetics
Phosphatidylinositol 3-Kinases / genetics
Phosphoinositide-3 Kinase Inhibitors*
Poly(ADP-ribose) Polymerases / metabolism
Protein Serine-Threonine Kinases / drug effects*
Quinolines / pharmacology*
Signal Transduction / drug effects
TOR Serine-Threonine Kinases

Substances

Enzyme Inhibitors
Imidazoles
Intracellular Signaling Peptides and Proteins
Phosphoinositide-3 Kinase Inhibitors
Quinolines
Poly(ADP-ribose) Polymerases
MTOR protein, human
Class I Phosphatidylinositol 3-Kinases
PIK3CA protein, human
Protein Serine-Threonine Kinases
TOR Serine-Threonine Kinases
PTEN Phosphohydrolase
PTEN protein, human
CASP9 protein, human
Caspase 9
dactolisib