Journal Article

The PI3 kinase/mTOR blocker NVP-BEZ235 overrides resistance against irreversible ErbB inhibitors in breast cancer cells

Zielinski, Christoph C., Grunt, Thomas W., Brünner-Kubath, Caroline, Saferding, Victoria, Valent, Peter, Berger, Walter, Marian, Brigitte, Wagner, Renate, Grusch, Michael, Shabbir, Waheed, Singer, Christian F.

2011

نظرة عامة

Resistance against first and second generation (irreversible) ErbB inhibitors is an unsolved problem in clinical oncology. The purpose of this study was to examine the effects of the irreversible ErbB inhibitors pelitinib and canertinib on growth of breast and ovarian cancer cells. Although in vitro growth-inhibitory effects of both drugs exceeded by far the effects of all reversible ErbB blockers tested (lapatinib, erlotinib, and gefitinib), complete growth inhibition was usually not reached. To define the mechanism of resistance, we examined downstream signaling pathways in drug-exposed cells by Western blot analysis. Although ErbB phosphorylation was reduced by pelitinib and canertinib, activation of the AKT/mTOR pathway remained essentially unaltered in drug-resistant cells. Correspondingly, transfection of tumor cells with constitutively activated AKT was found to promote resistance against all ErbB inhibitors tested, whereas dominant negative AKT reinstalled sensitivity in drug-resistant cells. In a next step, we applied PI3K/AKT/mTOR blockers including the dual PI3K/mTOR kinase inhibitor NVP-BEZ235. These agents were found to cooperate with pelitinib and canertinib in producing in vitro growth inhibition in cancer cells resistant against ErbB-targeting drugs. In conclusion, our data show that ErbB drug-refractory activation of the PI3K/AKT/mTOR pathway plays a crucial role in resistance against classical and second-generation irreversible ErbB inhibitors, and NVP-BEZ235 can override this form of resistance against pelitinib and canertinib.

• الناشر: Springer US,Springer,Springer Nature B.V,Springer Verlag
• موضوع: Aminoquinolines - pharmacology / Aniline Compounds - pharmacology / Antineoplastic Agents - pharmacology / Biological and medical sciences / Blotting, Western / Breast cancer / Breast Neoplasms - enzymology / Breast Neoplasms - pathology / Cancer cells / Cancer research / Cancer therapies / Cell Line, Tumor / Cell Proliferation - drug effects / Dose-Response Relationship, Drug / Drug resistance / Drug Resistance, Neoplasm / Enzyme Activation / Female / Female genital diseases / Gynecology. Andrology. Obstetrics / Humans / Imidazoles - pharmacology / Mammary gland diseases / Medical sciences / Medicine / Medicine & Public Health / Molecular Targeted Therapy / Morpholines - pharmacology / Oncology / Ovarian cancer / Ovarian Neoplasms - enzymology / Ovarian Neoplasms - pathology / Phosphatidylinositol 3-Kinase - antagonists & inhibitors / Phosphatidylinositol 3-Kinase - metabolism / Phosphorylation / Preclinical Study / Protein Kinase Inhibitors - pharmacology / Proto-Oncogene Proteins c-akt - genetics / Proto-Oncogene Proteins c-akt - metabolism / Quinolines - pharmacology / Receptor, Epidermal Growth Factor - antagonists & inhibitors / Receptor, Epidermal Growth Factor - metabolism / Signal Transduction - drug effects / Time Factors / TOR Serine-Threonine Kinases - antagonists & inhibitors / TOR Serine-Threonine Kinases - metabolism / Transfection / Tumors